Treatment of sexual dysfunction and for improved sexual quality of life

ABSTRACT

Compositions and methods for treating sexual dysfunction and enhancing sexual satisfaction using topical application of alpha-1 adrenergic receptor agonists, muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors are disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This is a continuation-in-part application of, and claims the benefit of, PCT/US/2016/036970 filed on Jun. 10, 2016, which claims the benefit of U.S. Provisional Application No. 62/317,698 filed on Apr. 4, 2016, 62/297,598 filed on Feb. 19, 2016, U.S. Provisional Application No. 62/222,494 filed on Sep. 23, 2015, U.S. Provisional Application No. 62/213,927 filed on Sep. 3, 2015, U.S. Provisional Application No. 62/211,470 filed on Aug. 28, 2015, U.S. Provisional Application No. 62/203,728 filed on Aug. 11, 2015, U.S. Provisional Application No. 62/188,233 filed on Jul. 2, 2015, U.S. Provisional Application No. 62/175,806 filed on Jun. 15, 2015, and U.S. Provisional Application No. 62/174,262 filed on Jun. 11, 2015, and the entire content of each application referenced above is incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to methods to treat sexual dysfunction, particularly female sexual dysfunction, and related disorders and conditions pertaining to sexual activity and sexual satisfaction, and methods to enhance sexual satisfaction, particularly female sexual satisfaction.

BACKGROUND DISCUSSION

Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women. There are few treatment options. See Kyan J. Allandadi et al., “Female Sexual Dysfunction: Therapeutic Options and Experimental Challenges,” Cardiovasc Hematol Agents Med Chem. 2009 Oct. 7 (4): 260-269. FSD can be classified under many subtypes. For example, female sexual arousal disorder (FSAD) is a disorder characterized by a persistent inability to attain sexual arousal or to maintain arousal until the completion of a sexual activity. Female Sexual Interest/Arousal Disorder (FSIAD) is a diagnosis found when a subject experiences a lack of or significantly reduced sexual interest or arousal. Female hypoactive sexual desire disorder (FHSDD) is a general loss of interest in sexual activity. Other subtypes exist, for example, anorgasmia, a difficulty achieving orgasm.

Currently, off-label use of testosterone has been prescribed. A therapy approved by the FDA in August 2015 is the Sprout Pharmaceuticals, Inc. product Addyi™ (flibanserin 100 mg), a once-daily, non-hormonal pill for the treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. In addition, there are several drugs that were the subject of clinical trials that affect signaling in the brain. See Wright, J. J., O'Connor, K. M. (2015), “Female sexual dysfunction,” Medical Clinics of North America, 99(3), 607-628. Because both hormonal and psycho-affective drugs can be associated with serious negative side effects, alternative treatment options would be desired for treating this prevalent condition.

The arousal phase of the female sexual response cycle involves genital mechanisms, such as clitoral, labial, and vaginal engorgement, as well as non-genital peripheral mechanisms, such as increases in body secretions, cutaneous vasodilation, and nipple sensitivity with or without nipple erection. Nipple sensitivity and erection occurs via activation of adrenergic nerves and the cholinergic nerves. It has been shown in pigs that both adrenergic and cholinergic neurons innervate the mammary gland. Smooth muscles in the nipple areola complex are contracted, thereby erecting the nipple. Agonists of the adrenergic receptors directly stimulate the smooth muscle. Acetylcholine and acetylcholine receptor agonists act via axon reflexes to stimulate smooth muscle contraction. Acetylcholine acts on the nerves in the central nervous system as a substance mediating the propagation of impulses across the ganglionic synapse, but it also has a second pharmacological effect, which is mediated through an axon reflex. Axon reflexes are peripheral nervous system impulses independent of the central nervous system. See Rothman and Coon, “Axon Reflex Responses to Acetyl Choline in the Skin,” J. Investigative Dermatology, 3: 79-97 (1940). Additionally, the mammary glands and the nipple are ducts. Acetylcholine directly stimulates ducts.

The role of nipple stimulation in influencing sexual desire and arousal in women prior to and during intercourse has been reported in the literature. Eighty-two percent of surveyed women report that stimulation of their nipples caused or enhanced their sexual arousal. See Levin, R., Meston, C. (2006), “Nipple/Breast stimulation and sexual arousal in young men and women,” Journal of Sexual Medicine, 3(3), 450-454; Levin, R. (2006), “The breast/nipple/areola complex and human sexuality,” Sexual and Relationship Therapy, 21(2), 237-249. In addition, stimulation of a women's nipple has been shown to correlate with increased oxytocin levels in blood serum. See Stein, J. L., Bardeguez, A. D., Verma, U. L., Tegani, N. (1990), “Nipple stimulation for labor augmentation,” Journal of Reproductive Medicine, 35(7), 710-714. Oxytocin is a peptide hormone shown to play a role in sexual satisfaction and desire.

In addition to sexual dysfunctions described above, women may have low sexual interest, desire or arousal, fewer and/or less intense orgasms, or general lack of sexual satisfaction due to a coexisting medical or psychiatric condition, such as women who have had breast surgery that reduces or eliminates sensitivity at the nipple-areola complex. There is a need for pharmaceutical treatment to restore or increase sensitivity in such subjects.

U.S. Pat. No. 4,853,216 (Koslo et al.) reports topical application of alpha-1 adrenergic receptor agonists (“A1AR agonists”) to a hair-bearing skin area to facilitate the physical or chemical handling of the hair. The purpose is to activate the pilomotor effect and erect the hair on the skin. This may be applied as a pretreatment prior to shaving or incorporated into a shaving composition, such as shaving cream. U.S. Pat. No. 4,853,216 discloses that suitable A1AR agonists include phenylephrine and methoxamine. See U.S. Pat. No. 4,853,216 at col. 2 lines 46-48. WO2004041259 (Thurlow et al.) describes the use of alpha-1adrenergic receptor antagonists for the treatment of FSD. The reference does not describe application of the antagonist to at least a portion of the nipple-areola complex, and focuses rather on inhibitors of receptors in the vaginal tissue. It is unexpected from this teaching that an A1AR agonist would be useful for treatment of FSD when applied to at least a portion of the nipple-areola complex.

A1AR agonists bind to α1-receptors on vascular smooth muscle and induce smooth muscle cell contraction, thus mimicking the effects of sympathetic neuron activation of smooth muscles via adrenergic receptors. Phenylephrine is a selective A1AR agonist. Phenylephrine is used as a decongestant, for which it is sold as an oral medicine or a nasal spray. Phenylephrine is also sold as a topical ointment to prevent or reduce symptoms of hemorrhoids. Phenylephrine is used as an eye drop to dilate the pupil to facilitate visualization of the retina. US Patent Application Pub. 2004/0198706 (Carrara et al.) discloses formulations for providing transdermal or transmucosal delivery of active agents. The formulations treat symptoms of hormonal disorders including female sexual desire disorder. The active agents may be selected from a large group of therapeutic agents, one of which is phenylephrine. The reference does not describe application of the transdermal or transmucal dosage forms to the nipple-areola complex. It is unexpected from this teaching that an MAR agonist such a phenylephrine would be useful for treatment of FSD when applied to the nipple-areola complex.

SUMMARY

The present disclosure concerns a method of increasing sexual satisfaction in a female subject comprising applying a therapeutically effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of the female subject, such as in one further embodiment a female subject who has undergone breast surgery that resulted in reduced nipple sensation. In another embodiment, the present disclosure concerns a method of treating sexual dysfunction, in some embodiments a method of treating female sexual dysfunction, the method comprising applying a therapeutically effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of a subject, such as a female subject, in need of such treatment. In another embodiment, the disclosure concerns a method of reducing or alleviating a symptom of sexual dysfunction, in some embodiments a symptom of female sexual dysfunction, the method comprising applying a therapeutically effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of a subject, such as a female subject, in need of such treatment. In a further embodiment, the disclosure concerns a method of causing erection of nipples, increasing nipple sensitivity, increasing duration of orgasm, reducing time to orgasm, and/or increasing oxytocin release related to sexual activity in a subject, in some embodiments a female subject, comprising applying an effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of the subject. In one embodiment, the method is to increase nipple sensitivity in a female subject that had breast surgery. The disclosure also concerns compounds and compositions for use in any of the methods disclosed herein.

BRIEF DESCRIPTION OF THE FIGURE(S)

FIG. 1 is a diagram identifying areas of the nipple-areola complex. FIG. 1 shows points corresponding to the four areolar quadrants (P1-P4) and the nipple (P5), in right and left breasts. P1, areola superolateral point; P2, areola superomedial point; P3, areola inferomedial point; P4, areola inferolateral point; P5, nipple.

DETAILED DESCRIPTION Methods of Use

The present disclosure relates to methods to treat or reduce sexual dysfunction and related disorders pertaining to sexual activity and sexual satisfaction, and methods to enhance or increase sexual satisfaction, in some embodiments female sexual satisfaction. The present disclosure also relates to methods to treat women having reduced sensitivity of the breast or particularly of the nipple-areola complex, such as treating women having reduced or absent sensitivity at the nipple-areola complex, to increase their sexual satisfaction, to increase sexual self-confidence, to increase nipple sensitivity, to increase duration of orgasm, to reduce time to orgasm, to increase intensity of orgasm, and to improve sexual quality of life.

As used herein, the terms “female sexual dysfunction” or “FSD” refer generally to the impairment of the sexual function in a female. Sexual dysfunction in females includes inhibited orgasm. Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including female hypoactive sexual desire disorder (FHSDD or HSDD, used interchangeably herein), female orgasmic disorder (FOD), sexual anhedonia, female sexual interest/arousal disorder (FSIAD), and female sexual arousal disorder (FSAD). Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties. Sexual anhedonia includes decreased or absent pleasure in sexual activity. Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents. The woman can experience mild, moderate, or severe FSD.

In one embodiment, FSD, FSAD, FOD and FHSDD are as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), 4th edition, the contents of which definitions are incorporated herein by reference. In another embodiment, the disorder is female sexual interest/arousal disorder (FSIAD), which encompasses FSAD and FHSDD. FOD and FSIAD are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), 5th edition, the contents of which definitions are hereby incorporated herein by reference. The diagnostic criteria for FSIAD include a lack of, or significantly reduced, sexual interest/arousal, as manifested by at least three of the following: (1) absent/reduced interest in sexual activity; (2) absent/reduced sexual/erotic thoughts or fantasies; (3) no/reduced initiation of sexual activity, and typically unreceptive to a partner's attempts to initiate; (4) absent/reduced sexual excitement/pleasure during sexual activity in almost all or all sexual encounters; (5) absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues; and (6) absent/reduced genital or nongenital sensations during sexual activity in almost all or all sexual encounters. In FSIAD, these symptoms have persisted for a minimum duration of approximately six months and cause the subject significant distress. The diagnostic criteria for FOD are as follows:

A. Presence of either of the following symptoms and experienced on almost all or all (approximately 75%-100%) occasions of sexual activity (in identified situational contexts or, if generalized, in all contexts): (1). Marked delay in, marked infrequency of, or absence of orgasm. (2). Markedly reduced intensity of orgasmic sensations.

B. The symptoms in Criterion A have persisted for a minimum duration of approximately 6 months.

C. The symptoms in Criterion A cause clinically significant distress in the individual.

D. The sexual dysfunction is not better explained by a nonsexual mental disorder or as a consequence of severe relationship distress (e.g., partner violence) or other significant stressors and is not attributable to the effects of a substance/medication or another medical condition.

The diagnosis of FOD also asks the clinician to specify whether (1) Lifelong: The disturbance has been present since the individual became sexually active or (2) Acquired: The disturbance began after a period of relatively normal sexual function. Also, the clinician is to specify whether (1) Generalized: Not limited to certain types of stimulation, situations, or partners or (2) Situational: Only occurs with certain types of stimulation, situations, or partners. The clinician is to specify if the subject never experienced an orgasm under any situation. The clinician is also to specify the current severity: (1) Mild: Evidence of mild distress over the symptoms in Criterion A, (2) Moderate: Evidence of moderate distress over the symptoms in Criterion A, (3) Severe: Evidence of severe or extreme distress over the symptoms in Criterion A. As reported in the Diagnostic and Statistical Manual of Mental Disorders (DSM), 5th edition, page 431, selective serotonin reuptake inhibitors (SSRIs) are known to delay or inhibit orgasm in women.

According to certain of the methods disclosed herein, to treat female sexual dysfunction disorder(s) or to enhance female sexual satisfaction, a topical composition of an active agent is applied to the woman's nipple-areola complex. In one aspect of the invention there is a method of treating FSD, preferably FSIAD, FSAD, FSOD, or FHSDD, comprising administering to a subject in need of such treatment an effective amount of an active agent as defined herein topically to the nipple-areola complex. As used herein, applying a composition to a nipple-areola complex includes applying to the nipple, the areola, or both the nipple and the areola, and to all or a portion of the nipple, the areola, or both the nipple and the areola. For example, the composition may be applied to the areola area only, the base of the nipple only, to half the areola only or applied to more than half of the areola and not the nipple. In one embodiment, the composition is applied to only one of a subject's nipple-areola complexes. The term “nipple-areola complex” or “NAC” includes both the nipple and areola. The nipple-areola complex varies in dimension among individuals. The female nipple-areola complex is located at the prominence of the breast mound. See Anongporn Nimboriboonporn, “Nipple-areola complex reconstruction,” Gland Surgery 2014; 3(1), pp. 35-42. The nipple itself may project as much as greater than or equal to 1 cm, with a diameter of approximately 4-7 mm. The areola consists of pigmented skin surrounding the nipple proper and is on average approximately 4.2-4.5 cm in diameter. The smooth muscle morphology in the nipple-areola complex is described, for example, in M. Tezer, et al., “Smooth muscle morphology in the nipple-areola complex,” J. Morphol. Sci., 2011, vol. 28, no. 3, p. 171-175.

In other embodiments, the invention is directed to methods of increasing female sexual satisfaction, causing erection of nipples, increasing nipple sensitivity, increasing duration of orgasm, reducing time to orgasm, increasing intensity of orgasm and/or increasing oxytocin release related to sexual activity by administering an active agent according to the present disclosure topically to the nipple areola complex of a female subject. In one particular embodiment, the invention is directed to methods of treating neuropathy, and particularly neuropathy at the nipple areola complex or just at the nipple. In other embodiments, the invention is directed to methods of increasing female sexual self-esteem and/or increasing a female subject's self-perception of femininity by administering an active agent according to the present disclosure topically to the nipple areola complex of a female subject. In another embodiment, the invention is directed to methods of increasing female self-esteem by administering an active agent according to the present disclosure topically to the nipple areola complex of a female subject.

Enhancement of female sexual satisfaction, female sexual self-esteem, female self-esteem, and female self-perception of femininity can be measured by patient questionnaires to determine if the subject's quality of life, particularly in sexual matters, is enhanced by the present therapeutic methods. Enhancement can also be determined by a change from baseline in the number of satisfying sexual events (SSE), a change from baseline in the level of sexual interest or desire, a change from baseline in the level of sexual arousal, or a change from baseline in the level of distress from sexual activities. Baseline may be defined as a four-week no-treatment phase or a four-week placebo run-in phase. Changes from baseline typically refer to the treatment responses obtained during the last four weeks of a double-blinded treatment period relative to baseline. The time period used for assessing baseline (e.g., four weeks) should be the same as the time period used for assessing treatment responses (e.g., four weeks at the end of the treatment period). Enhancement of self-esteem or female sexual self-esteem may be measured by any one of the questionnaires and scales available in the art such as, without limitation, those disclosed in Heatherton, T. F. & Polivy, J. (1991) “Development and validation of a scale for measuring state self-esteem,” J. Personality and Social Psychology, 60, 895-910; Rosenberg's Self-Esteem Scale found on Oct. 30, 2016 at http://www.wwnorton.com/college/psych/psychsci/media/rosenberg.htm; and Rosenberg self-esteem scale published in Rosenberg, M. “Society and the adolescent self-image,” Princeton University Press, Princeton, N.J. (1965). In one embodiment, the questionnaire is completed by the female subject at a time prior to application of the active agent and prior to one or more episodes of sexual intimacy, and then the questionnaire is completed again by the same subject after the application of the active agent and the occurrence of one or more episodes of sexual intimacy.

In one embodiment, the women subjects to be treated by the methods described herein have reduced sensitivity of the nipple-areola complex. Sensitivity may be considered as reduced relative to (1) sensitivity measured in a control group, such as a control group of women of comparable age, sexual activity, and health, particularly breast health or nerve health, to those undergoing the treatment or (2) sensitivity as measured before an event, such as before an operation, injury, or other biological change to a breast or a nipple-areola complex. Any of the known techniques for measuring breast sensitivity may be used to determine if the subject presents with reduced sensitivity. For example, studies have measured the sensitivity of the nipple-areola complex to pressure before and after mammoplasty with a superomedial pedicle. See, e.g., Ferreira, M C et al., “Sensibility of the breast after reduction mammoplasty,” Ann Plast Surg 2003; 51 (1):1-5. A quantitative analysis of post-operative changes in breast sensitivity and female sexual function was reported in Garcia, E S et al., “Sensitivity of the nipple-areola complex and sexual function following reduction mammoplasty,” Aesthetic Surgery Journal 35(7) (2015) NP193-NP202. In Garcia et al., skin sensitivity tests were performed in a quiet environment and the nipple-areola complex was tested for four sensory modalities: light touch, temperature (hot and cold), vibration, and pressure. Id. at NP194. Sensitivity was measured using Semmes-Weinstein filaments (SORRI, BAURU, SP, Brazil, INPI.7.102.105), corresponding to threshold/potential skin pressure values of 0.05, 0.2, 2, 4, 10, and 300 grams (Garcia, at FIG. 2). The monofilament was used to exert pressure until it bent, and the pressure was maintained for 5 seconds. The perceived pressure value was recorded. Pressure response of less than 9 g/mm² was considered sensitive, and greater than 9 g/mm² was considered to show reduced sensitivity.

In one embodiment, the invention is directed to methods for the manufacture of compositions, particularly pharmaceutical compositions, for the treatment or reduction of any of the disorders or conditions recited herein comprising mixing the active agent with a pharmaceutically acceptable excipient, such as water, mineral oil, or a surfactant.

In one embodiment, the method comprises (1) applying an active agent selected from the group consisting of alpha-1 adrenergic receptor agonists (e.g., without limitation, synephrine), muscarinic acetylcholine receptor agonists (e.g., without limitation, non-specific or specific agonists of (a) muscarinic acetylcholine receptor M₃ and/or of (b) muscarinic acetylcholine receptor M₂), nicotinic acetylcholine receptor agonists, the acetylcholine receptor agonist neuropeptide-Y, and cholinesterase inhibitors on a test site on the skin of a person; wherein the test site is not in the nipple areola complex; and (2) 30 to 60 minutes after applying, observing whether the person's skin shows goosebumps or pilioerection at the site; wherein if pilioerection or goosebumps are observed, then diagnosing the person as likely to be a successful candidate for use of the alpha-1 adrenergic receptor agonist, muscarinic acetylcholine receptor agonist, nicotinic acetylcholine receptor agonist, neuropeptide-Y, or cholinesterase inhibitor for any of the many methods of treatment or prevention described herein. This method may be combined with any of the other methods of treatment or prevention described herein to provide an initial diagnosis of those people most likely to benefit from the treatment and enhancement methods described. In such combination methods, the treatment steps only proceed if the person's skin shows goosebumps or pilioerection at the test site. The step of application to a site on the skin may be, in one embodiment, applying a bandage or patch coated with the active agent selected from the group consisting of alpha-1 adrenergic receptor agonists, muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, acetylcholine receptor agonist that is neuropeptide-Y, and cholinesterase inhibitors to the person's arm or thigh. In other embodiments of any composition or method involving an alpha-1 adrenergic receptor agonist, the agonist is synephrine or phenylephrine.

The subjects to be treated with the present invention include humans, and in certain embodiments are pre-, per- and post-menopausal women or men. In one embodiment, the woman is concomitantly on hormone replacement therapy. In another embodiment she is not on concomitant hormone replacement therapy. The methods disclosed may be useful for women who have diminished or absent breast sensation, such as women having low nipple sensitivity, or having reduced sensitivity at the nipple-areola complex. Low sensitivity is a sensitivity below the average, such as below one standard deviation, obtained from a representative sample of subjects, for example by measuring nipple sensitivity in a healthy population of women using the monofilament test described herein. A sensitivity value may be obtained by measuring sensitivity on several locations on the nipple areola complex and averaging them. In one embodiment, the women being treated have low nipple sensitivity after breast surgery, which as used herein includes breast implants.

In one preferred embodiment, the subjects to be treated are women who have experienced breast surgery, particularly women who after breast surgery experience reduced or absent nipple sensitivity. The breast surgery may be of any type, such as without limitation mastectomy, nipple sparing mastectomy, skin-sparing mastectomy, prophylactic mastectomy, breast reconstruction, breast augmentation, and lumpectomy. For women who have experienced breast surgery, successful therapy in the present methods can be determined by measuring increased sensitivity in the NAC, such as by quantitative measurement using the monofilament test disclosed above in Garcia et al., or the test in the examples herein, or by patient reports of increased quality of life, such as by increased sexual satisfaction as shown using one or more of the measurements or patient reports discussed herein. In another embodiment, the disclosed methods may be used in women with high breast or nipple-areola sensitivity, such as to enhance sexual satisfaction. In one further embodiment, the subjects to be treated are women with neuropathy, in particular women with neuropathy at the nipple areola complex.

In another embodiment, the subjects to be treated is a mammal, such as non-human primates (particularly higher primates), sheep, dog, rodent (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cow, and panda. Treatment in non-human mammals may be desirable to accelerate conception during mating. Treatment may also be desirable to induce labor in a mammal, including a human.

In one embodiment, the subject to be treated is a human or animal concomitantly taking one or more SSRI or antidepressants, such as antidepressants used in the treatment of major depressive disorder and anxiety disorders. SSRIs may cause a variety of sexual dysfunction, such as anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm). To minimize or reduce these side effects, one of the active agents of the present disclosure according to any of the methods of administration disclosed herein may also be administered to the subject concomitantly with the SSRI therapy. By “concomitantly” is meant herein to be administered in the same day, week or month, not necessarily at the same time of day, however. SSRIs include the following: citalopram, fluvoxamine, escitalopram, paroxetine, sertraline, fluoxetine, and dapoxetine. The compositions and methods of the present disclosure may also be used with a subject who concomitantly is taking tricyclic antidepressants or serotonin-noradrenaline reuptake inhibitors (SNRIs). Examples of SNRIs include the following: venlafaxine; desvenlafaxine, duloxetine, milnacipran, levomilnacipran, and sibutramine.

The active agents described herein may be applied once every one, two, three, four, six, eight, ten or twelve hours, or once daily, twice daily, or once every other day. The frequency of administration may be determined by one skilled in the art using pharmacokinetic data available or generated using standard procedures. Routine pharmacological testing may be performed to determine if dosages of more than once or twice daily are advisable and if so the amount of each dosage, in view of the potential for a rebound effect. It should be noted that increased sexual arousal can be delayed with respect to nipple erection after the application of the composition described herein. For example, increased sexual arousal can occur about 10-45 minutes after nipple erection or increased nipple sensitivity. The formulations of active agent described herein may be applied as needed. In one embodiment, the formulation is applied prior to a sexual activity, such as about 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, or 6.0 hours prior to sexual activity, or between 0.25-1.0, 0.5-1.0, 0.5-1.5, 1.0-2.0, or 1.0-4.0 hours prior to sexual activity. Examples of sexual activities include, but are not limited to, foreplay, sexual intercourse, and masturbation. In case of sensitivity of the nipple-areola complex to the formulation, it may be advisable that following use the next administration occur after 48-72 hours has passed. In another embodiment, the active agent first exerts its effect within about ten minutes of application to the nipple-areola complex. In further embodiments, the active agent first exerts its effects between five and thirty minutes after application. In one embodiment, the active agent exerts an effect on the nipple-areola complex for a time period of about one-two hours after application, or from about ten minutes to about one hour, or from about ten minutes to about two hours, or from about ten minutes to about three hours after application.

As used herein, the terms “treat,” “treatment,” or “treating” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a disease or condition, e.g., FSD. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a disease or condition, e.g., FSD. Treatment is generally “effective” if one or more symptoms are reduced. That is, “treatment” includes the improvement of symptoms. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s) and diminishment of extent of disease. For example, treatment of FSD is considered effective if the number of satisfying sexual events (SSE) is increased from baseline in a sampled time (e.g. 4 weeks), in a significant manner. Other established metrics to determine treatment efficacy for FSD include, for example, FSFI (female sexual function index), SAL (Sexual Activity Log), SAR (Sexual Activity Record), FSDS (Female Sexual Distress Scale), and the FSDS-R (Female Sexual Distress Scale Revised). Treatment may occur even if nipple erection is not obtained. Setting the smooth muscle underlying the nipple-areola complex without nipple erection is believed sufficient to elicit the desirable biological response in a subject, such as a female subject, and therefore to “treat” or “enhance” according to the methods disclosed herein.

In one embodiment, a therapeutic effect is seen when the difference from baseline is a “minimally important difference” or “MIN” defined in: DeRogatis, L. R., Graziottin, A., Bitzer, J., Schmitt, S., Koochaki, P. E., Rodenberg, C. (2009), “Clinically relevant changes in sexual desire, satisfying sexual activity and personal distress as measured by the profile of female sexual function, sexual activity log, and personal distress scale in postmenopausal women with hypoactive sexual desire disorder,” Journal of Sexual Medicine, 6, 175-183, the contents of which are incorporated herein by reference. Such a change may be small but meaningful to subjects.

Active Agents

Useful active agents for the methods of use disclosed herein include agonists of muscarinic acetylcholine receptors (mAChRs), agonists of nicotinic acetylcholine receptor (also referred to herein as nicotinic receptors or nAChRs), acetylcholine receptor agonists such as neuropeptide-Y, and cholinesterase inhibitors. The agonists may be selective or nonselective agonists of mAChRs or nAChRs. In other embodiments, a prodrug that is activated to become a mAChR or nAChR agonist or a cholinesterase inhibitor can be utilized. Any of the active agents disclosed herein may be used in combination with another active agent disclosed herein, including in combination with another active agent of the same type (such as without limitation one muscarinic acetylcholine receptor agonist in combination with a second muscarinic acetylcholine receptor agonist) or in combination with a different type of active agent (such as without limitation a muscarinic acetylcholine receptor agonist with a nicotinic acetylcholine receptor agonist). By “combination” is meant that the active agents are applied within about one hour of each other to the skin, or at substantially the same time to the skin, or otherwise such that the combined active agents are expected to show effect on the NAC at the same time.

Muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs) are acetylcholine receptors of an autonomic nervous system that can be manipulated by agonists.

mAChRs are found in tissues innervated by postganglionic parasympathetic neurons, in presynaptic noradrenergic and cholinergic nerve terminals, in non-innervated sites in vascular endothelium, and in the central nervous system. There are subtypes of muscarinic receptors, which are typically referred to as M₁ (e.g., M₁, M₂, M₃, M₄, and M₅). Muscarinic receptor agonists that may be used to treat sexual dysfunction and increase sexual satisfaction according to the present compositions and methods include without limitation NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium, methacholine, aceclidine, pilocarpine, and muscarine. It has been discovered that at least M₂-type agonists and M₃-type agonists can be used to induce direct smooth muscle contraction.

Suitable M₂ agonists for the compositions and methods of the present disclosure include, but are not limited to, methacholine, (2S,2′R,3′S,5′R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, [³H]oxotremorine-M, NNC 11-1585, NNC 11-1607, pentylthio-TZTP, methacholine, NNC 11-1314, xanomeline, oxotremorine, acetylcholine, arecaidine propargyl ester, carbachol, McN-A-343, arecoline, methylfurmethide, pilocarpine, furtrethonium, bethanechol, iperoxo, aceclidine, [18F]FP-TZTP, and berberine. Suitable M₃ agonists for the compositions and methods of the present disclosure include, but are not limited to, NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium, methacholine, aceclidine, L-689,660 (mixed M₁/M₃ agonist), and pilocarpine.

Nicotinic acetylcholine receptors are located in sympathetic and parasympathetic ganglia, in the adrenal medulla, in the neuromuscular junction of the skeletal muscle, and in the central nervous system. Nicotinic acetylcholine receptors are ligand-gated ion channels whose activation results in a rapid increase in cellular permeability to sodium and calcium. They are pentameric arrays of one to four distinct but homologous subunits, surrounding an internal channel. The a subunit, which has binding sites for ACh, is present in at least two copies. Agonist molecules induce a conformational change that opens the channel. Antagonist molecules may bind to these sites, but do not elicit the conformational change.

There are at least two subtypes of nicotinic receptors, generally referred to as N_(M) and N_(N). The N_(M) nicotinic receptor mediates skeletal muscle stimulation, while the N_(N) nicotinic receptor mediates stimulation of the ganglia of the autonomic nervous system. Useful nicotinic receptor agonists to treat sexual dysfunction and the other conditions and disorders disclosed herein include without limitation: varenicline tartrate, galantamine hydrobromide, nicotine, carbachol, suxamethonium chloride (succinylcholine chloride), and epibatidine.

In another embodiment, the active agent useful for treatment of the disorders and diseases described herein is neuropeptide-Y, which is an acetylcholine receptor agonist. In one embodiment, the present disclosure concerns one of the methods disclosed herein, such as a method for treating sexual dysfunction, particularly female sexual dysfunction, comprising applying a therapeutically effective amount of an active agent selected from the group consisting of neuropeptide-Y, muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of a female subject in need of such treatment.

In another embodiment, the active agent used in the inventive methods herein is an A1AR agonist. “Alpha-1 adrenergic receptor agonist” or “A1AR agonist” refers to a ligand that binds the alpha-1adrenergic receptor on smooth muscle cells and activates smooth muscle contraction. In some embodiments, the AIAR agonist is selective for the alpha-1adrenergic receptor. Additionally, the term “alpha-1 adrenergic receptor agonist” can include agents that when applied will induce the release of endogenous alpha-1 adrenergic receptor agonists (e.g. epinephrine) that activates smooth muscle contraction or agents that when applied inhibit the “re-uptake” or degradation of endogenous alpha-1adrenergic receptor agonists (e.g. epinephrine) that activates smooth muscle contraction. In another embodiment, the active agent used is a “smooth muscle agonist,” which is an agent that promotes or results in contraction of the smooth muscle including smooth muscle of the nipple-areola complex. Thus, an alpha-1adrenergic receptor agonist that promotes or results in smooth muscle contraction is a smooth muscle agonist, but so also are, e.g., an alpha 2 adrenergic receptor agonist that promotes smooth muscle contraction, agents that that induce the release of endogenous alpha 2 adrenergic receptor agonist that results in smooth muscle contraction, and agents that inhibit the re-uptake or degradation of endogenous alpha 2 adrenergic receptor agonists that activate smooth muscle contraction. Suitable A1AR agonists for use in the present description include without limitation phenylephrine, phenylephrine pivalate, amediphrine, synephrine, cirazoline, desvenlafaxine, etilfrine, metaraminol, methoxamine, naphazoline, oxymetazoline, pseudoephrine, m-synephrine, p-synephrine, octopamine, hordenine, tetrahydrozoline, isometheptene, metaraminol, nicergoline, ergonovine, levonordefrin, phendimetrazine, methoxamine, midodrine, clonidine, pergolide, xylometazoline, droxidopa, epinephrine, mephentermine, 4-methoxyamphetamine, benzphetamine, naphazoline, apraclondine, bromocriptine, oxymetazoline, phenylpropanolamine, pseudoephedrine, dipivefrin, noradrenaline, chloroethylclonidine, norepinephrine, A61603, NS-49, [¹²⁵I]HEAT, noradrenaline, adrenaline, clonidine, St 587, SKF 89748, 6-fluoro-noradrenaline, methylnoradrenaline, inanidine, NS-49, amidephrine, and dabuzalgron and dopamine. In certain embodiments, the A1AR agonist is synephrine, or is selected from phenylephrine, synephrine, oxymetazoline, and methoxamine. In one embodiment, the therapeutic agent is norepinephrine. Another suitable therapeutic agent for use in the inventive methods herein is extract of Bitter orange (Citrus aurantium), which contains synephrine alkaloids and para-octopamine. See Satoh, Y., Tashiro, S., Satoh, M., Fujimoto, Y., Xu, J. Y., and Ikekawa, T. [Studies on the bioactive constituents of Aurantii Fructus Immaturus]. Yakugaku Zasshi 1996; 116(3):244-250. In one embodiment, the method is for treating neuropathy in a female subject comprising administering a therapeutically effective amount of an A1AR agonist, such as without limitation phenylephrine, to the female subject.

Additionally, derivatives of alpha-1adrenergic receptor agonists, muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, or cholinesterase inhibitors can be utilized including derivatives of the compounds mentioned above. In other embodiments, a prodrug that is activated to become an A1AR agonist, muscarinic acetylcholine receptor agonist, nicotinic acetylcholine receptor agonist, or cholinesterase inhibitor can be utilized. Midodrine, phenylephrine oxazolidine, and phenylephrine pivalate are examples of three such prodrugs. Phenylephrine pivalate is an A1AR agonist in addition to being a prodrug of phenylephrine. A particular prodrug can be activated by endogenous enzymes in the skin such as Caspase-1. Another embodiment is a method for reducing or ceasing erection of the nipple following administration of alpha-1 adrenergic receptor agonist(s) comprising applying a therapeutically effective amount of an alpha-1adrenergic receptor antagonist or a beta adrenergic receptor agonist to the nipple areola complex. Such a method may be useful, for example, in the event of an overdose of alpha-1adrenergic receptor agonist.

As used herein, a “prodrug” refers to compounds that can be converted via some chemical or physiological process (e.g., enzymatic processes and metabolic hydrolysis) to an active agent. Thus, the term “prodrug” also refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, i.e. an ester, but is converted in vivo to an active compound, for example, by hydrolysis to the free carboxylic acid or free hydroxyl. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in an organism. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. See Harper, “Drug Latentiation” in Jucker, ed. Progress in Drug Research 4:221-294 (1962); Morozowich et al, “Application of Physical Organic Principles to Prodrug Design” in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APHA Acad. Pharm. 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Pharmacokinet., 15(2): 143-53 (1990); Balimane and Sinko, “Involvement of multiple transporters in the oral absorption of nucleoside analogues”, Adv. Drug Delivery Rev., 39(1-3): 183-209 (1999); Browne, “Fosphenytoin (Cerebyx)”, Clin. Neuropharmacol. 20(1): 1-12 (1997); Bundgaard, “Bioreversible derivatization of drugs—principle and applicability to improve the therapeutic effects of drugs,” Arch. Pharm. Chemi 86(1): 1-39 (1979); Bundgaard H. “Improved drug delivery by the prodrug approach,” Controlled Drug Delivery 17: 179-96 (1987); Bundgaard H. “Prodrugs as a means to improve the delivery of peptide drugs,” Arfv. Drug Delivery Rev. 8(1): 1-38 (1992); Fleisher et al. “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs,” Arfv. Drug Delivery Rev. 19(2): 115-130 (1996); Fleisher et al. “Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting,” Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81, (1985); Farquhar D, et al., “Biologically Reversible Phosphate-Protective Groups,” Pharm. Sci., 72(3): 324-325 (1983); Freeman S, et al., “Bioreversible Protection for the Phospho Group: Chemical Stability and Bioactivation of Di(4-acetoxy-benzyl) Methylphosphonate with Carboxyesterase,” Chem. Soc., Chem. Commun., 875-877 (1991); Friis and Bundgaard, “Prodrugs of phosphates and phosphonates: Novel lipophilic alphaacyloxyalkyl ester derivatives of phosphate- or phosphonate containing drugs masking the negative charges of these groups,” Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al., “Pro-drug, molecular structure and percutaneous delivery,” Des. Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21. (1977); Nathwani and Wood, “Penicillins: a current review of their clinical pharmacology and therapeutic use,” Drugs 45(6): 866-94 (1993); Sinhababu and Thakker, “Prodrugs of anticancer agents,” Adv. Drug Delivery Rev. 19(2): 241-273 (1996); Stella et al., “Prodrugs. Do they have advantages in clinical practice?” Drugs 29(5): 455-73 (1985); Tan et al. “Development and optimization of anti-HIV nucleoside analogs and prodrugs: A review of their cellular pharmacology, structure-activity relationships and pharmacokinetics,” Adv. Drug Delivery Rev. 39(1-3): 117-151 (1999); Taylor, “Improved passive oral drug delivery via prodrugs,” Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino and Borchardt, “Prodrug strategies to enhance the intestinal absorption of peptides,” Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus, “Concepts for the design of anti-HIV nucleoside prodrugs for treating cephalic HIV infection,” Adv. Drug Delivery Rev.: 39(I-3):63-80 (1999); Waller et al., “Prodrugs,” Br. J. Clin. Pharmac. 28: 497-507 (1989), which are incorporated by reference herein in their entireties.

Other agents or approaches can be used to contract the smooth muscle to erect nipples for the treatment of FSD or the enhancement of sexual satisfaction. As noted above, any agent or treatment that stimulates smooth muscle contraction is of potential use in methods of treating FSD or enhancing sexual satisfaction as described herein.

In another embodiment, the smooth muscle of the nipple-areola complex can be contracted by stimulating or activating a cold receptor. This is believed to stimulate the pilomotor reflex to result in contraction of the smooth muscle and erection of the nipple. A cold receptor can be stimulated, for example, by activating the TRPM8 channel. Exemplary agents that can stimulate a cold receptor include, but are not limited to, menthol and icilin. Compositions and methods for stimulating a cold receptor are disclosed, for example, in U.S. Pat. No. 4,034,109 (Rowsell et al.).

Without limiting the invention in any way, it is believed that the smooth muscle in and surrounding the nipple areola complex is served by or associated with both noradrenergic fibers and a cholinergic system, and therefore agents that stimulate release of transmitters from these systems or that activate the axon reflex can be used to stimulate smooth muscle contraction and thereby increase sensitivity in the nipple areola complex. Thus, alpha-1adrenergic agonists and cholinergic receptor agonists, including, but not limited to acetylcholine and other neurotransmitters that stimulate smooth muscle contraction are contemplated for use in the methods and compositions described herein. The alpha-1adrenergic receptor is a postsynaptic G protein-coupled receptor on the surface of smooth muscle cells. Agonists of other G protein-coupled receptors involved in smooth muscle contraction (e.g., post-synaptic alpha 2 adrenergic receptors) can also be used to stimulate contraction of the smooth muscles and thus erection of the nipple when applied to the nipple-areola complex. Examples of agonists of the postsynaptic alpha 2 adrenergic receptor include but are not limited to, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, brimonidine, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tizanidine, tolonidine, xylazine, brimonidine, amitraz, chloroethylclonidine and xylometazoline. In some embodiments, an antagonist of the presynaptic alpha 2 adrenergic receptor that inhibits negative feedback of noradrenaline release from the presynaptic neuron can also be used to stimulate smooth muscle cell contraction. Such antagonists include aripiprazole, asenapine, atipamezole, cirazoline, clozapine, efaroxan, idazoxan, lurasidone, melperone, minserin, mirtazapine, napitane, olanzapine, paliperidone, phenyoxybenzamine, phentolamine, piribedil, rauwolscine, risperidone, rotigotine, quetiapine, norquetiapine, setipiline, tolazoline, yohimbine, ziprasidone, and zotepine. In some embodiments, an alpha-1agonist/alpha 2 partial agonist, such as oxymetazoline, is contemplated for use with the methods described herein. To the extent that it would be disadvantageous to administer these or other agents systemically, they can be administered in a formulation that permits uptake by the smooth muscle of at least a portion of the nipple-areola complex in the dermis but limits systemic uptake.

The muscarinic and nicotinic receptor agonists mimic acetylcholine effect by stimulating the relevant receptors themselves or by acting through the axon reflex. Another way of accomplishing the same thing is to reduce the destruction of acetylcholine (Ach) following its release. This can be achieved by cholinesterase inhibitors, which are also called the anticholinesterases. They mimic the effect of combined muscarinic and nicotinic agonists. By inhibiting acetylcholinesterase and pseudocholinesterase, these drugs allow ACh to build up at its receptors. Thus, they result in enhancement of both muscarinic and nicotinic agonist effect. Suitable cholinesterase inhibitors for the present methods and compositions include without limitation physostigmine, neostigmine, edrophonium, pyridostigmine, echotihiophate, ambenonium, demecarium, tacrine, donepezil, rivastigmine, galantamine, and pralidoxime.

The glands in the NAC respond to Ach. Without intending to be limited, it is believed the present inventive methods and compositions work by the mechanism that agonists of the muscarinic receptors, particularly agonists of the muscarinic receptor types M₂ and M₃, and cholinesterase inhibitors induce response in the NAC through the activity of the cholinergic pathway on the mammary glands and ducts of the nipple and therefore induce the desired sexual response.

It should be noted that the agonists and inhibitors described herein also encompass their pharmaceutically acceptable inorganic or organic salts. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, succinate, valerate, oleate, palm itate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. For example, phenylephrine may be administered in its hydrochloride salt form.

Formulations and Dosages

The present disclosure also pertains to pharmaceutical compositions of the active agents discussed herein. The formulations or compositions of the present disclosure include a therapeutically effective amount of one or more active agents and a pharmaceutically acceptable excipient. Formulation guidance may be found in Remington: The Science and Practice of Pharmacy, Pharmaceutical Press (2012), Allen (ed.). The compositions may be of any sort useful for topical delivery to the nipple-areola complex, such as, without limitation, a gel, cream, emulsion, transdermal patch, spray, foam, ointment, or aerosol. In one preferred formulation, the composition is a gel. In some embodiments, the active agent is present in a transdermal patch that is sized and designed to fit smoothly around the nipple. The transdermal patch may provide immediate release or sustained release of the active agent. In another embodiment, the active agent is applied to a substrate such as a bandage having an exterior and an interior surface, where the interior surface is coated with the active agent and a surrounding adhesive section. The adhesive section preferably is adjacent to, but not comingled with, the coating of active agent. The substrate is then applied to the nipple areola complex such that the interior surface of the substrate is placed on the skin and active agent is in contact with the nipple areola complex. In one embodiment, this substrate is shaped like a donut with a circular shape having a central circle cut-out. The coated substrate is applied to the nipple-areola complex such that much of the nipple (at least 50%) is not in contact with the therapeutic agent because the nipple extends through the hole in the bandage. This embodiment is particularly desirable for patients for whom the nipple is particularly sensitive. In this embodiment, the substrate is ring shaped and comprises two surfaces, an exterior and an interior surface, the exterior surface preferably comprising a water-resistant plastic coating and the interior surface coated with the active agent along a central portion closest to the center of the ring and a circumferential surface extending along the broadest circumference of the substrate that contains an adhesive that provides adhesion, removably, to human skin surface. The active agent present on the substrate may be in a formulation that is a gel, solution, cream, etc. In one of these embodiments, the substrate coated with active agent is applied to the areola for 10, 15, 20, 25, 30, 40, or 45 minutes and then removed, or for less than 10, less than 15, less than 20, less than 25, less than 30, or less than 45 minutes and then removed. The substrate may be disposed after application. In other embodiments, the active agent can be included in ointments or other topical creams that could be applied to at least a portion of the nipple-areola complex so that it can be absorbed into the skin and stimulate the smooth muscle. In other embodiments, the active agent can be in a liquid spray or aerosol medium, such as a metered spray, such as is found for example in Evamist® estradiol transdermal spray. The spray may contain an alcohol, water, or a water/alcohol mixture as a vehicle for the active agent.

In some embodiments, the composition is provided in a delivery device that has a roller ball connected to a container holding the composition such that the composition may be applied to the nipple-areola complex by rolling the ball directly on the complex. For example, the roller ball device may have a generally cylindrical container that holds a liquid formulation of one or more active agents therein and has an open upper end and a lower end. A roller ball is rotatably disposed in the container and protrudes from the upper end of the container. A cap portion has a closed upper end and an open lower end. The lower end of the cap portion is removably coupled to the upper end of the container. Devices such as these are well known in the art. See, e.g., U.S. Pat. No. 6,095,708 (Butaud); U.S. Pat. No. 5,007,775 (Thompson); U.S. Pat. No. 4,664,547 (Rosenwinkel); U.S. Design Pat. No. 333,977 (Gatrost); and U.S. Design Pat. No. 292,069 (Keeler).

In one embodiment, the compositions are formulated for quick delivery through the dermis to the smooth muscles, such as for delivery of 60%, 70%, 75%, 80%, 85% or more of the active agent through the dermis within 5, 4, 3, 2 or 1 hour of application to the nipple-areola complex. In another embodiment, at least 80% of the active agent is delivered through the dermis on average after three hours as measured with an in vitro release test using a Franz cell such as discussed in the examples herein.

Formulations may be prepared according to the knowledge and skill of those in the art. In some embodiments, the compositions can further comprise a flavoring agent. One example of the flavoring agent is a sweetening agent, such as monoammonium glycyrrhizinate. In liquid and gel formulations, the bulk excipient that serves as a medium for conveying the active ingredient is the vehicle. Suitable vehicles for topical gels and creams include petrolatum and mineral oil.

Penetration enhancers may be used in the present compositions to increase the permeability of the dermal surface to a active agent, and are often proton accepting solvents such as dimethyl sulfoxide (DMSO) and dimethylacetamide. Chemical permeation enhancers facilitate drug permeation across the skin by increasing drug partitioning into the barrier domain of the stratum corneum and/or increasing drug diffusivity in the barrier domain of the stratum corneum. Several mechanisms of action are known: increasing fluidity of stratum corneum lipid bilayers, extraction of intercellular lipids, increase of drug's thermodynamic activity, increase in stratum corneum hydration, alteration of proteinaceous corneocyte components and others. Permeation enhancers are conventionally divided into several groups based on their chemical structure rather than the mechanism of action. More than 300 substances have been shown to have skin permeabilization potential. Enhancers fall into the following general categories: alcohols (ethanol, pentanol, benzyl alcohol, lauryl alcohol, propylene glycols and glycerol), fatty acids (oleic acid, linoleic acid, valeric acid and lauric acid), amines (diethanolamine and triethanolamine), esters (isopropyl palmitate, isopropyl myristate and ethyl acetate), amides (1-dodecylazacycloheptane-2-one [Azone®], urea, dimethylacetamide, dimethylformamide and pyrrolidone derivatives), hydrocarbons (alkanes and squalene), surfactants (sodium laureate, cetyltrimethylammonium bromide, Brij® nonionic polyoxyethylene surfactant, Tween® polyol and sodium cholate), terpenes (D-limonene, carvone and anise oil), sulfoxides (dimethyl sulfoxide) and phospholipids (lecithine). Hydration of the stratum corneum is important. A fully hydrated stratum corneum (under occlusion) presents lesser diffusional resistance to a drug than its dehydrated counterpart.

In some embodiments, the composition further comprises an exfoliating agent to promote abrasion of the surface of the skin to increase the permeability of the dermal surface to a therapeutic agent. Examples of the exfoliating agent include (1) inorganic and/or metallic particles such as: boron nitride, in body-centered cubic form (Borazon®); aluminosilicate (e.g. nepheline); zircon; mixed oxides of aluminum such as emery; zinc oxide; aluminum oxides such as aluminas or corundum; titanium oxide; titanium oxide coated mica; carbides, in particular silicon carbide (carborundum); or other metal oxides; metals, and metal alloys such as iron shot, steel shot, and in particular perlite; silicates such as glass, quartz, sand, or vermiculite; calcium carbonate (e.g. Bora-Bora sand or Rose de Brignoles sand) or magnesium carbonate; sodium chloride; pumice stone; amorphous silica; diamond; ceramics, and (2) organic particles such as: fruit stones, in particular apricot stones, e.g. Scrubami® apricot; wood cellulose, e.g. ground bamboo stem; coconut shell, e.g. coconut exfoliator; polyam ides, in particular Nylon-6; sugars; plastic microbeads, e.g. polyethylenes or polypropylenes; ground walnut; ground apricot seed; ground shells, and (3) mixed particles associating organic and inorganic compounds, and particles coated in the above compounds. The exfoliating agents may be in the form of microbeads of less than five millimeters in its largest dimension that have an exfoliating effect.

In one embodiment, the active agent is incorporated into capsules or other slow release vehicles in the composition that allow the chemical or agent to be slowly released into the dermis. Capsules or vehicles that encapsulate the active agent can include, but are not limited to, liposomes, non-ionic liposomes, niosomes, novasome I, erythromycin-Zn complex, microspheres, nanoparticles, solid lipid nanoparticles, and nanoemulsions.

The dosage applied to each nipple-areola complex on a female or male patient will be specific for the different active agents disclosed herein. One of ordinary skill may use standard practices and testing to determine an acceptable dosage. In one embodiment, the dosage applied on a nipple-areola complex is between 0.1-15, 10-15, 5-20, 10-20, 0.1-5.0, 0.2-0.8, 0.4 -5.0, 0.4-4.0, 0.4-3.0, 0.4-2.0, 0.4-1.0, 0.4-0.8, 0.6-5.0, 0.6-4.0, 0.6-3.0, 0.6-1.0, 1.0-5.0, 1.0-4.0, 1.0-3.0, 1.0-2.0, 1.5-5.0, 1.5-4.0, 1.5-3.0, 1.5-2.0, 1.5-3.5, 0.1-2.0, 0.2-2.0, 0.3-2.0, 0.5-2.0, 0.6-2.0, 0.7-2.0, 0.8-2.0, 0.9-2.0, 1.1-2.0, 1.2-2.0, 1.3-2.0, 1.4-2.0, 1.5-2.0, 1.6-2.0, 1.7-2.0, 1.8-2.0, or 1.9-2.0 mg/cm² of active agent. In one embodiment, the active agent is phenylephrine, oxymetazoline or synephrine and the dosage applied on a nipple-areola complex is between 0.05-5.0, 0.1-5.0, 0.4 -5.0, 0.4-4.0, 0.4-3.0, 0.4-2.0, 0.4-1.0, 0.4-0.8, 0.6-5.0, 0.6-4.0, 0.6-3.0, 0.6-1.0, 1.0-5.0, 1.0-4.0, 1.0-3.0, 1.0-2.0, 1.5-5.0, 1.5-4.0, 1.5-3.0, 1.5-2.0, 1.5-3.5, 0.1-2.0, 0.2-2.0, 0.3-2.0, 0.5-2.0, 0.6-2.0, 0.7-2.0, 0.8-2.0, 0.9-2.0, 1.1-2.0, 1.2-2.0, 1.3-2.0, 1.4-2.0, 1.5-2.0, 1.6-2.0, 1.7-2.0, 1.8-2.0, or 1.9-2.0 mg/cm². In one embodiment the dosage of the active agent is 0.1-2.0, 0.5-2.0, 1.0-2.0, 0.1-1.0, 0.2-1.0, 0.3-1.0, 0.4-1.0, 0.5-1.0, 0.6-1.0, 0.7-1.0, 0.8-1.0, 0.9-1.0, 0.1-0.9, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.3-0.9, 0.3-0.8, 0.3-0.7, 0.4-0.9, 0.4-0.8, 0.5-0.9, 0.5-0.8, 0.5-0.7, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg/cm². In one embodiment when the active agent is phenylephrine, methoxamine or oxymetazoline, the dosage of the active agent is 0.1-2.0, 0.5-2.0, 1.0-2.0, 0.1-1.0, 0.2-1.0, 0.3-1.0, 0.4-1.0, 0.5-1.0, 0.6-1.0, 0.7-1.0, 0.8-1.0, 0.9-1.0, 0.1-0.9, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.3-0.9, 0.3-0.8, 0.3-0.7, 0.4-0.9, 0.4-0.8, 0.5-0.9, 0.5-0.8, 0.5-0.7, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg/cm². In another embodiment the active agent is phenylephrine HCl and the dosage is 0.1-2.0, 0.5-2.0, 1.0-2.0, 0.1-1.0, 0.2-1.0, 0.3-1.0, 0.4-1.0, 0.5-1.0, 0.6-1.0, 0.7-1.0, 0.8-1.0, 0.9-1.0, 0.1-0.9, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.3-0.9, 0.3-0.8, 0.3-0.7, 0.4-0.9, 0.4-0.8, 0.5-0.9, 0.5-0.8, 0.5-0.7, or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg/cm². Under this dosage measurement, a smaller dimension of the nipple-areola complex will result in a lower total dose.

As measured by in vitro release testing (IVRT), the dosage that penetrates the stratum may be about 90, 80, 70, 60, 50, 40 or 30% of the dosage topically applied. In one embodiment, the dosage that penetrates the stratum is between 0.1-1.0, 0.2-1.0, 0.3-0.9, 0.4-0.8, 0.5-1.0, 0.6-1.1, 0.01-1.0, or 0.01-0.1 mg/cm², or is approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9 mg/cm².

The active agent can be applied in a transdermal patch of any appropriate size and formulation that allows for administration of a therapeutically effective amount of one or more active agents. In one embodiment, the nipple-areola complex may be measured and a circle of the appropriate size of a transdermal patch applied to encompass the entire nipple-areola surface. In certain embodiments, the circular transdermal patches are 8, 12 and 16 cm in diameter. In other embodiments, the circular transdermal patch is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cm in diameter, or is a size ranging from 5-10, 6-11, 7-12, 8-13, 9-14, 10-15, 11-16, 12-17, 13-18, 14-19, or 15-20 cm in diameter. Based on a transdermal patch or occlusive covering of a therapeutic composition of 8 cm in diameter, a total dosage of 5 mg may be applied in one embodiment. Similarly, a patch 12 cm in diameter may apply a total dose of 7.5 mg and a patch of 16 cm may apply a total dose of 10 mg.

In one embodiment, the active agent is present in the composition for topical administration at a concentration of 0.025-1.0, 0.05-1.0, 0.025-2.0, 0.05-2.0, 0.05-3.0, 0.05-4.0, 0.5-1.0, 0.5-2.0, 0.5-3.0, 0.1-40.0, 0.1-35.0, 0.1-25.0, 0.1-10.0, 0.1-15.0, 0.1-5.0, 1.0-25.0, 1.0-10.0, 1.0-15.0, 1.0-5.0, 5.0-25.0, 5.0-10.0, 5.0-15.0, 5.0-10, 5.0-15.0, 5.0-20.0, 10.0-20.0, 20.0-30.0, 25.0-30.0, 30.0-40.0, 10.0-40.0, or 35.0-40.0% by weight, or approximately 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, or 40% by weight. In one embodiment, the active agent is phenylephrine, synephrine or a pharmaceutically acceptable salt or hydrate thereof and is in a composition at a concentration of 5% to 10% or 10% to 30% therapeutic agent by total weight of the composition. In one embodiment, the composition comprises an A1AR agonist in a concentration of about 0.25, 0.33, 0.5, 1.0, 2.0 or 2.5% by weight. In one embodiment, the composition comprises methoxamine or oxymetazoline (such as oxymetazoline HCl) in a concentration of about 0.025-1.0, 0.05-1.0, 0.025-2.0, 0.05-3.0, 0.05-5.0, 0.05-4.0, 0.1-5.0 or 0.5-2.0% by weight or in a concentration of about 0.025, 0.05, 0.25, 0.33, 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0% by weight. In one embodiment, the active agent is midodrine and is present in the composition at a concentration of 0.025-5.0, 0.05-5.0, 0.1-5.0, 0.2-5.0, 0.025-2.0, 0.05-2.0, 0.2-2.0 or 0.1-3.0% by weight. As is readily understood by the person of ordinary skill in the field, the concentration of active agent in a composition can vary depending on the particular active agent used and the efficacy of the composition containing it to deliver the agent through the dermis.

In one embodiment, the method is to treat female sexual dysfunction, preferably female sexual arousal disorder (FSAD), female sexual interest/arousal disorder (FSIAD), female orgasmic disorder (FOD) or female hypoactive sexual desire disorder (FHSDD), by applying a therapeutically effective amount of one or more active agents selected from the following: an A1AR agonist, such as phenylephrine; a muscarinic acetylcholine receptor agonist; a nicotinic acetylcholine receptor agonist; and a cholinesterase inhibitor, topically to a nipple-areola complex of a female subject in need of such treatment, such as a premenopausal woman, in an amount of 0.2-0.8 mg/cm² active agent per surface area of the nipple-areola complex. In another embodiment, the method is to treat treating female sexual dysfunction, preferably female sexual arousal disorder (FSAD), female sexual interest/arousal disorder (FSIAD), female orgasmic disorder (FOD) or female hypoactive sexual desire disorder (FHSDD), by applying a therapeutically effective amount of one or more active agents from the following: an A1AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and a cholinesterase inhibitor, topically to a nipple-areola complex of a female subject in need of such treatment, such as a postmenopausal woman, in an amount of 0.2-0.8 mg/cm² therapeutic agent per surface area of the nipple-areola complex. In a further embodiment, the method is to reduce or alleviate a symptom of female sexual dysfunction, such as (1) absent/reduced interest in sexual activity; (2) absent/reduced sexual/erotic thoughts or fantasies; (3) no/reduced initiation of sexual activity, and typically unreceptive to a partner's attempts to initiate; (4) absent/reduced sexual excitement/pleasure during sexual activity in almost all or all sexual encounters; (5) absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues; or (6) absent/reduced genital or nongenital sensations during sexual activity in almost all or all sexual encounters, the method comprising applying a therapeutically effective amount of one or more active agents selected from the following: an A1AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and a cholinesterase inhibitor, in a dosage of 0.2-0.8 mg/cm², topically to a nipple-areola complex of a female subject in need of such treatment. In yet a further embodiment, the method is for causing erection of nipples, increasing nipple sensitivity, and/or increasing oxytocin release related to sexual activity in a female subject, such as a premenopausal or postmenopausal woman, comprising applying an effective amount of one or more active agents selected from the following: an A1AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and a cholinesterase inhibitor, topically to a nipple-areola complex of the female subject in an amount of 0.2-0.8 mg/cm².

In yet another embodiment, the method is to treat female sexual dysfunction, preferably female sexual arousal disorder (FSAD), female sexual interest/arousal disorder (FSIAD), female orgasmic disorder (FOD) or female hypoactive sexual desire disorder (FHSDD), by applying a therapeutically effective amount of one or more active agents selected from the following: an A1AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and/or a cholinesterase inhibitor topically to a nipple-areola complex of a female subject in need of such treatment, such as a premenopausal woman. In at least one embodiment, the method is to reduce or alleviate a symptom of female sexual dysfunction, such as (1) absent/reduced interest in sexual activity; (2) absent/reduced sexual/erotic thoughts or fantasies; (3) no/reduced initiation of sexual activity, and typically unreceptive to a partner's attempts to initiate; (4) absent/reduced sexual excitement/pleasure during sexual activity in almost all or all sexual encounters; (5) absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues; or (6) absent/reduced genital or nongenital sensations during sexual activity in almost all or all sexual encounters, the method comprising applying a therapeutically effective amount of one or more active agents selected from the following: an A1AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and/or a cholinesterase inhibitor. In yet a further embodiment, the method is for causing erection of nipples, increasing nipple sensitivity, and/or increasing oxytocin release related to sexual activity in a female subject, such as a premenopausal or postmenopausal woman, comprising applying an effective amount of one or more active agents selected from the following: an Al AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and a cholinesterase inhibitor.

The pH of the formulation will be determined following procedures known in the art to provide for stability of the active agent and allow for skin penetration of the agent. Phenylephrine, for example, may be formulated at a pH of less than 6, particularly if it is concentrated at 10% or more by weight of the formulation. In one embodiment, phenylephrine is formulated at 10% by weight or higher in a liquid solution that does not contain ethanol and has a pH of less than 6, preferably 5.5 or between 4.9 and 5.5, 4.9 and 5.6, 4.9 and 5.7, 4.9 and 5.8, 4.9 and 5.9, 5.0 and 5.8, 5.0 and 5.9, 5.1 and 5.8, 5.1 and 5.7, 5.2 and 5.8, 5.3 and 5.8, 5.3 and 5.7, or 5.4 and 5.6.

The term “consisting of” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

As used herein the term “consisting essentially of” refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment.

The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.”

Measurement of the strength of nipple smooth muscle contraction can be performed, if necessary, via myograph adapted for that purpose. Examples are described in, e.g., Zeveke & Gladysheva, Bull. Exp. Biol. Med. 71: 102-105 (1971) and Hellmann, J. Physiol. 169: 603-620 (1963). Measurement of nipple sensitivity can be performed, if necessary, via Semmes-Weinstein monofilament test adapted for that purpose. Other methods for measuring nipple sensitivity (i.e., sensibility) have been described. Examples are described in, e.g., Mofid, Dellon, Elias & Nahabedian, Plast Reconstr Surg. 109(7):2283-2288 (2002).

Efficacy of treatment for FSD and enhancement of sexual satisfaction can be determined by monitoring the number of satisfying sexual events (SSE) in a given experimental period. For example, a questionnaire may be administered by a clinician asking the number of SSEs a patient has experienced in a given four-week period. A treatment can thus be applied for another four-week period and the questionnaire can be re-assessed at the end of the treatment. An increase in SSE from baseline can then be evaluated, for example, in a statistically significantly large cohort. As but one example, an average increase from 6 to 6.7 SSEs would show efficacy of a treatment. Similarly, secondary endpoints could include questionnaires assessing sexual satisfaction, e.g., change from baseline to end-of-study in arousal domain score, female sexual function index, satisfaction with arousal, desire domain from female sexual function index, satisfaction with desire, quality of relationship with partner, and a female sexual distress scale. Other established metrics to determine treatment efficacy for FSD can also be used, and they include, for example, FSFI (female sexual function index), SAL (Sexual Activity Log), SAR (Sexual Activity Record), FSDS (Female Sexual Distress Scale), and the FSDS-R (Female Sexual Distress Scale Revised).

Other parameters to measure or quantify sexual arousal in females include arousal domain score from female sexual function index, satisfaction with arousal, desire domain from female sexual function index, satisfaction with desire as measured, quality of relationship with partner, change in hormone levels such as oxytocin, length of time of nipple erection. A treatment is considered effective if any one or a combination of these parameters is increased as compared to a reference level that is measured in the absence of the treatment.

Active agents can optionally be administered by iontophoresis, which uses an electric field to drive the passage of ionic agents or drugs into the skin. As but one example, iontophoresis has been used to deliver agents such as phenylephrine to the skin to stimulate smooth muscle contraction. See, e.g., Siepmann et al., Neurology Apr. 25, 2012; 78(Meeting Abstracts 1): P05.197. Thus, in one embodiment, the present disclosure relates to an iontophoresis device for transdermal delivery that dispenses one or more active agents that are selected from the following: A1AR agonists, such as phenylephrine; muscarinic acetylcholine receptor agonists; nicotinic acetylcholine receptor agonists; and cholinesterase inhibitors. The iontophoresis device can comprise one or more metal contacts. Optionally, the iontophoresis device can comprise one or more compartments for containing the active agent(s). For example, the iontophoeresis device can comprise one or more compartments for containing at least one of an A1AR agonist, a muscarinic receptor agonist, a nicotinic receptor agonist, and a cholinesterase inhibitor.

Penetration enhancement of the active agents across the stratum corneum can be achieved by applying an electric field gradient across the skin. This iontophoresis method is well established in the literature. See Nitin Dixit, Vikas Bali, Sanjula Baboota, Alka Ahuja and Javed Ali (2007), “Iontophoresis—An Approach for Controlled Drug Delivery: A Review”, Current Drug Delivery, 4, 1-10. For example, phenylephrine hydrochloride, a selective alpha-1adrenergic receptor agonist, has been successfully iontophorised across the stratum corneum and delivered to the arrector pili muscle producing piloerection on the forearm. See T. Siepmann, C. H. Gibbons, B. M. Illigens, J. A. Lafo, C. M. Brown, and R. Freeman (2012), “Quantitative Pilomotor Axon-Reflex Test—A Novel Test of Pilomotor Function”, Archives of Neurology (2012), 69(11), 1488-1492. The advantage of using iontophoresis is that the concentrations of active agent required to penetrate the stratum corneum are typically much lower than those needed with other topical formulations. For example, a 1% w/v concentration of phenylephrine hydrochloride can activate the piloerection on the forearm when iontophoresis in used. See T. Siepmann, Archives of Neurology (2012), supra.

In one embodiment of the present invention, a solution of one or more active agents that are selected from the following: A1AR agonists, such as phenylephrine; muscarinic acetylcholine receptor agonists; nicotinic acetylcholine receptor agonists; and cholinesterase inhibitors is placed in an iontophoresis patch specifically designed for the nipple areola complex. Devices such as these are well known in the art. See, e.g., U.S. Pat. No. 8,442,629 B2 (Suzuki); U.S. Pat. No. 4,968,297 A (Jacobsen); US Patent U.S. Pat. No. 8,362,027 B2 (Inagi); U.S. Pat. No. 4,419,092 A (Jacobsen); U.S. Pat. No. 8,423,131 B2 (Mir Imran); U.S. Pat. No. 5,087,242 A (Tomasz); U.S. Pat. No. 5,248,295 A (Jacobsen). It is important to note that the net charge of the drug must be matched with the like charged terminal of the iontophoretic device. For example, if a solution of phenylephrine hydrochloride is used, the solution should be placed on the positively charged electrode of the iontophoresis patch. During iontophoresis, an electric field drives the charged drug molecules across the stratum corneum. This method of delivering the active agent that is an A1AR agonist, such as phenylephrine, a muscarinic acetylcholine receptor agonist, a nicotinic acetylcholine receptor agonist, and/or a cholinesterase inhibitor on or in an iotophoresis patch is believed to be useful with any of the inventive methods of use disclosed herein, as is apparent to one of ordinary skill in the art.

In one embodiment of the invention, electroporation is used to enhance the permeability of the stratus corneum. During electroporation, an electric current is applied to the skin, creating pores in the stratum corneum that facilitate diffusion of the drug molecules. The drug may diffuse across the stratum corneum by static diffusion. In an embodiment, electroporation is combined with iontophoresis, and the drug is further driven through the stratus corneum by an electric field. It should be understood that electroporation may be used to enhance permeability of any of the therapeutic compositions disclosed herein, with or without the added use of iontophoresis.

In one embodiment of the invention, a voltage of about 30 V to about 500 V are applied to the skin for electroporation. In an embodiment, the voltage is pulsed for a short duration. In some embodiments, the short duration is in a range of greater than 0 ms to about 300 ms.

Electrical Stimulation

In one embodiment of the invention, the smooth muscle can be contracted via electrical stimulation to at least a portion of the nipple-areola complex of the breast. The electrical stimulation can be controlled, e.g., by a unit. Examples of applying electrical forces to contract the smooth muscles are described in, for example, US Patent Application Pub. US2013/0199348 published on Aug. 8, 2013, titled Pilomotor Effect Stimulating Device and Method. In some embodiments, the voltage or amplitude of the signal applied can be in the range of 35 to 75 volts, 25 to 50 volts, 10 to 30 volts or other suitable ranges to reach the threshold for muscle contraction. The current applied by a device as disclosed herein can, in some embodiments, preferably be in the microamps to avoid electrocution of the user. A frequency of 10 KHz to 15 KHz can be applied, or a lower or higher frequency. In some embodiments, the pulse length applied will be from 1 to 50 milliseconds, 1 to 100 milliseconds, or other suitable lengths to contract smooth muscle of at least a portion of the nipple-areola complex or any other pilomotor effective amount of current. In some embodiments, a control unit will automatically pulse the electrical stimulation at random intervals that are enough to keep the smooth muscle relatively contracted. In other embodiments, the pulses will be spaced out enough to allow the smooth muscle to relax in between pulses.

In one embodiment, the electrical stimulation device can be built into a bra. A female subject can wear the bra with the electrical stimulation device and promote stimulation by turning on the device.

It should be noted that combinations of the above methods and active agents can be used to promote the contraction of the smooth muscle and achieve the desired therapeutic results and enhancement of sexual satisfaction.

The various methods and techniques described above provide a number of ways to carry out the invention. Of course, it is to be understood that not necessarily all objectives or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features.

All patents, patent applications, publications of patent applications, and other published material, such as articles and books referenced herein are hereby incorporated herein by this reference in their entireties. Should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail.

EXAMPLES

The following examples illustrate some embodiments and aspects of the invention. It will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be performed without altering the spirit or scope of the invention, and such modifications and variations are encompassed within the scope of the invention as defined in the claims which follow. The technology disclosed herein is further illustrated by the following examples which in no way should be construed as being further limiting.

Example 1 Transdermal Delivery of 10% Phenylephrine Solution

Transdermal penetration of a particular formulation can be assessed with in vitro release testing (IVRT) using a Franz cell. See Bartosova and Bajagar, “Transdermal Drug Delivery In Vitro Using Diffusion Cells,” Current Medicinal Chemistry, 2012, 19, 4671-4677.

In order to determine the dermal absorption and bioavailability of topically applied 10% Phenylephrine Hydrochloride solution, we used an IVRT experimental setup with both skin excised from pig ears and a synthetic skin model (Maine Manufacturing, LLC, Me., USA). In both models (see table below), the maximal skin absorption in 24 hours did not exceed 83%.

In the example, the following data was obtained from a Franz cell diffusion experiment using excised pigskin barrier. A 50 microliter aliquot of a phenylephrine solution was allowed to penetrate through 9 mm diameter sample of pigskin into a 5 mL reservoir of phosphate buffered saline. Phenylephrine concentration was determined in the reservoir by measuring the optical absorbance at 214 nm at time points subsequent to the application of the formulation. In the following example the test solution was 10% (w/w) phenylephrine, 10% (w/w) Dimethyl Isosorbide, and 80% (w/w) ethanol. From the data below, it can be concluded that the formulation can be deemed “successful” because 82% of the applied drug penetrated the pigskin membrane in 3 hours. The experiment was run in triplicate. The average of all three data is shown. It is envisioned that additional studies may be undertaken with other models of in vitro release testing or with variations of the same model to compare with the data reported below.

TABLE 1 IVRT skin penetration model (pig skin) of 10% Phenylephrine HCl solution. Penetration (%) Time (h) Sample 1 Sample 2 Sample 3 Average 1 32.3% 2.1% 0.7% 11.7% 2 80.6% 89.0% 13.6% 61.1% 3 78.9% 87.5% 81.9% 82.8% 4 78.6% 83.4% 81.1% 81.0% 5 78.5% 86.0% 81.3% 81.9% 24 81.3% 83.1% 80.3% 81.6%

Therefore, if a subject is to apply 0.1 mL of the drug solution and not remove it for a period of 24 hours (which is unlikely to occur), she will experience an average absorption of 8.3 mg of Phenylephrine HCl per nipple-areola complex or 16.6 mg total absorption over 24 hours. In comparison, in the United States, Over-the-Counter (OTC) Sudafed phenylephrine contains 10 mg phenylephrine hydrochloride oral tablets indicated for administration of 10 mg to 20 mg every 4 hours. The oral dosage is approximately 40% systemically bioavailable. Assuming one Sudafed® PE phenylephrine tablet every 4 hours or 60 mg per day, the total dosage will be 24 mg. The dosage proposed in the present study will result in approximately 45% less systemic Phenylephrine HCl exposure compared to the oral OTC drug.

In addition, while the percent of ocular absorption has not been determined, the 10% ophthalmic solution approved by the US FDA was found safe based on assuming complete absorption of 21 mg Phenylephrine HCl per day, which is also higher than the absorption at the dosage disclosed herein for the treatment of FSD.

Finally, it should be noted that systemic bioavailability of topically applied Phenylephrine HCl is likely to be far lower than the maximal estimated amount due to the local vasoconstriction effect of the drug; hence, the reduced systemic absorption.

Example 2

A study of the blood pressure and heart rate of five patients receiving topical application on the nipple-areola complex was made. The composition applied was 0.1 mL of a 10% phenylephrine solution for a total dosage of 10 mg phenylephrine HCl. Blood pressure and heart rate were measured at baseline (T=0), after 15 minutes and 30 minutes. No significant change in blood pressure or heart rate was detected in any of the subjects.

This data supports the safety of the topically applied dosage (˜15-20 mg) of phenylephrine. The applied dosage does not provide for an increase in systemic heart rate or blood pressure.

TABLE 2 0.1 mL 10% PHCI Subject Nr. BP (T = 0) BP (T = 15) BP (T = 30) HR (T = 0) HR (T = 15) HR (T = 30) 1 115/80 112/76 117/75 82 69 74 2 119/78 122/77 122/78 81 77 80 3 116/76 117/72 128/77 74 75 68 4 116/74 120/72 116/68 51 53 58 5 100/67  99/67 97/63 63 68 69

Example 3

A pilot study was conducted to assess the dosage of topical phenylephrine solution required to elicit nipple erection and sensitivity. Five subjects ages 18-70 participated in the study. Two subjects were post-menopausal and the reminder three were pre-menopausal. Subjects were not hypertensive, pregnant or breastfeeding. Three formulations were used: Formula A: 0% topical phenylephrine hydrochloride solution; Formula B: 5% topical phenylephrine hydrochloride solution; Formula C: 10% topical phenylephrine hydrochloride solution.

The study was conducted over 3 days. On day 1, subjects were instructed to apply on the left nipple Formula A and on the right nipple Formula B. On day 2, subjects were instructed to apply on the left nipple Formula A and on the right nipple Formula C. On day 3, subjects were instructed to apply on the left nipple Formula B and on the right nipple Formula C. 0.1 mL of each formula was applied with a cotton swab to the nipple areole complex. Table 3 summarizes the finding from this study. The 10% topical phenylephrine solution (Formula C) elicited a clinical response in all subjects while the 5% and placebo formulations (Formula A and B) failed to elicit a response. With the 10% topical phenylephrine solution, response in nipple erection and sensitivity was obtained in less than 30 minutes and lasted for 3-4 hours.

TABLE 3 Day 1 Day 2 Day 3 Subject Formula Formula Formula Formula Formula Formula Nr. A B A C B C 001 NR NR NR R NR R 002 NR NR NR R NR R 003 NR NR NR R NR R 004 NR NR NR R NR R 005 NR NR NR R NR R R = Response i.e., nipple erection NR = No Response

Example 4

An additional pilot study was conducted to assess the safety and efficacy of topical phenylephrine applied to the nipple-areole complex for the treatment of female sexual dysfunction. Nine women subjects ages 18-70 participated in the study. Two subjects were post-menopausal and the remaining seven were pre-menopausal. Subjects were not suffering from clinical depression, hypertension, pregnant, breastfeeding or currently taking testosterone, SSRIs, or other antidepressants. 0.1 mL of 10% topical phenylephrine hydrochloride solution was applied with a cotton swab to each nipple areole complex (a total dosage of 20 mg was applied topically). Subjects were instructed to apply the solution approximately 1 hour before sexual activity. The duration of the study was for a period of one week. The number of Satisfying Sexual Events (SSE) determined by a Sexual Activity Record (SAR) was recorded. In addition, a modified Female Sexual Function Index (FSFI) desire domain questionnaire was administered. Table 4 summarizes the change in SSEs from baseline as well as Adverse Events (AE). All subjects reported increased nipple sensitivity within 30 minutes after the application of the topical phenylephrine solution. The nipples remained sensitive up to 3 to 4 hours. In one subject, with initial slightly painful nipple erection, the sensitivity persisted for approximately 8 hours. Seven subjects reported significant change in the number of SSEs from baseline. Subjects reporting increase in the number of SSEs also reported increased desire possibly attributed to the hypothesized mechanism of action of oxytocin release as a result of nipple erection.

TABLE 4 Number of SSE Number of SSE Subject Nr. (baseline) (1 week) 001 1 3 002 0 2 003 0 1 004 2 4 005 1 3 006 2 2 007 1 1 008 3 6 009 2 3

Example 5 Protocols for Clinical Studies Primary Outcome Measures:

Number of satisfying sexual events (SSE) determined from Sexual Activity Record (SAR).

Secondary Outcome Measures:

Female Sexual Function Index (FSFI); Female Sexual Distress Scale, Revised (FSDS-R); Sexual Quality of Life-Female (SQOL-F).

Efficacy Parameters

During the first site visit, week 4 site visit and week 8 site visit, the primary investigator (PI) will instruct the subject in the use of the sexual activity record (SAR). In addition, during week 4 site visit and week 8 site final visit, the PI will administer standardized patient reported outcomes (PROs) of FSD.

PROs: Sexual Activity Record (SAR):

The SAR was developed to measure the frequency of successful and satisfactory sexual events as a primary end point in clinical trials of sexual dysfunction. The SAR is a brief form that is completed after the respondent engages in sexual activity. Its seven items assess the respondent's experience of the most recent sexual encounter in the areas of sexual arousal, orgasm, and overall satisfaction with sexual arousal. Respondents indicate whether sexual events include self-stimulation, partnered sexual activity, or a combination of both.

Female Sexual Function Index (FSFI):

The FSFI is a 19-item multidimensional self-report instrument (Table 5) used to assess women's sexual function in six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. The instrument yields scores for each of these six domains as well as a total score. The FSFI has demonstrated good test-retest reliability (a=0.79-0.88). Rosen et al., 2000, “The Female Sexual Function Index (FSFI): A multidimensional self-report instrument for the assessment of female sexual function,” Journal of Sex and Marital Therapy, 26, 191-208; Wiegel, M., Meston, C., & Rosen, R., 2005, “The Female Sexual Function Index: Cross-validation and development of clinical cut-off scores,” Journal of Sex & Marital Therapy, 31, 1-20.

TABLE 5 FSFI Question Response Options 1. Over the past 4 weeks, 5 = Almost always or always how often did you feel sexual 4 = Most times (more than half the time) desire or interest? 3 = Sometimes (about half the time) 2 = A few times (less than half the time) 1 = Almost never or never 2. Over the past 4 weeks, 5 = Very high how would you rate your level 4 = High (degree) of sexual desire or 3 = Moderate interest? 2 = Low 1 = Very low or none at all 3. Over the past 4 weeks, 0 = No sexual activity how often did you feel 5 = Almost always or always sexually aroused (“turned 4 = Most times (more than half the time) on”) during sexual activity 3 = Sometimes (about half the time) or intercourse? 2 = A few times (less than half the time) 1 = Almost never or never 4. Over the past 4 weeks, 0 = No sexual activity how would you rate your level 5 = Very high of sexual arousal (“turn 4 = High on”) during sexual activity 3 = Moderate or intercourse? 2 = Low 1 = Very low or none at all 5. Over the past 4 weeks, 0 = No sexual activity how confident were you about 5 = Very high confidence becoming sexually aroused 4 = High confidence during sexual activity or 3 = Moderate confidence intercourse? 2 = Low confidence 1 = Very low or no confidence 6. Over the past 4 weeks, 0 = No sexual activity how often have you been 5 = Almost always or always satisfied with your arousal 4 = Most times (more than half the time) (excitement) during sexual 3 = Sometimes (about half the time) activity or intercourse? 2 = A few times (less than half the time) 1 = Almost never or never 7. Over the past 4 weeks, 0 = No sexual activity how often did you become 5 = Almost always or always lubricated (“wet”) 4 = Most times (more than half the time) during sexual activity or 3 = Sometimes (about half the time) intercourse? 2 = A few times (less than half the time) 1 = Almost never or never 8. Over the past 4 weeks, 0 = No sexual activity how difficult was it to become 1 = Extremely difficult or impossible lubricated (“wet”) 2 = Very difficult during sexual activity or 3 = Difficult intercourse? 4 = Slightly difficult 5 = Not difficult 9. Over the past 4 weeks, 0 = No sexual activity how often did you maintain 5 = Almost always or always your lubrication (“wetness”) 4 = Most times (more than half the time) until completion of sexual 3 = Sometimes (about half the time) activity or intercourse? 2 = A few times (less than half the time) 1 = Almost never or never 10. Over the past 4 weeks, 0 = No sexual activity how difficult was it to 1 = Extremely difficult or impossible maintain your lubrication 2 = Very difficult (“wetness”) 3 = Difficult until completion of sexual 4 = Slightly difficult activity or intercourse? 5 = Not difficult 11. Over the past 4 weeks, 0 = No sexual activity when you had sexual 5 = Almost always or always stimulation or intercourse, 4 = Most times (more than half the time) how often did you reach 3 = Sometimes (about half the time) orgasm (climax)? 2 = A few times (less than half the time) 1 = Almost never or never 12. Over the past 4 weeks, 0 = No sexual activity when you had sexual 1 = Extremely difficult or impossible stimulation or intercourse, 2 = Very difficult how difficult was it for you 3 = Difficult to reach orgasm (climax)? 4 = Slightly difficult 5 = Not difficult 13. Over the past 4 weeks, 0 = No sexual activity how satisfied were you with 5 = Very satisfied your ability to reach orgasm 4 = Moderately satisfied (climax) during sexual activity 3 = About equally satisfied and or intercourse? dissatisfied 2 = Moderately dissatisfied 1 = Very dissatisfied 14. Over the past 4 weeks, 0 = No sexual activity how satisfied have you been 5 = Very satisfied with the amount of emotional 4 = Moderately satisfied closeness during sexual 3 = About equally satisfied and activity between you and your dissatisfied partner? 2 = Moderately dissatisfied 1 = Very dissatisfied 15. Over the past 4 weeks, 5 = Very satisfied how satisfied have you been 4 = Moderately satisfied with your sexual relationship 3 = About equally satisfied and with your partner? dissatisfied 2 = Moderately dissatisfied 1 = Very dissatisfied 16. Over the past 4 weeks, 5 = Very satisfied how satisfied have you been 4 = Moderately satisfied with your overall sexual life? 3 = About equally satisfied and dissatisfied 2 = Moderately dissatisfied 1 = Very dissatisfied 17. Over the past 4 weeks, 0 = Did not attempt intercourse how often did you experience 1 = Almost always or always discomfort or pain during 2 = Most times (more than half the time) vaginal penetration? 3 = Sometimes (about half the time) 4 = A few times (less than half the time) 5 = Almost never or never 18. Over the past 4 weeks, 0 = Did not attempt intercourse how often did you experience 1 = Almost always or always discomfort or pain following 2 = Most times (more than half the time) vaginal penetration? 3 = Sometimes (about half the time) 4 = A few times (less than half the time) 5 = Almost never or never 19. Over the past 4 weeks, 0 = Did not attempt intercourse how would you rate your level 1 = Very high (degree) of discomfort or pain 2 = High during or following vaginal 3 = Moderate penetration? 4 = Low = Very low or none at all

The individual domain scores and full scale (overall) score of the FSFI can be derived from the computational formula outlined in Table 4. For individual domain scores, add the scores of the individual items that comprise the domain and multiply the sum by the domain factor (see below). Add the six domain scores to obtain the full scale score. It should be noted that within the individual domains, a domain score of zero indicates that the subject reported having no sexual activity during the past month. Subject scores can be entered in the right-hand column. Significant positive changes in score reflect efficacy of the methods of treatment described herein.

TABLE 6 Score Minimum Maximum Domain Questions Range Factor Score Score Score Desire 1, 2 1-5 0.6 1.2 6.0 Arousal 3, 4, 5, 6 0-5 0.3 0 6.0 Lubrication 7, 8, 9, 10 0-5 0.3 0 6.0 Orgasm 11, 12, 13 0-5 0.4 0 6.0 Satisfaction 14, 15, 16 0 (or 1)-5 0.4 0.8 6.0 Pain 17, 18, 19 0-5 0.4 0 6.0 Full Scale Score Range 2.0 36.0

Female Sexual Distress Scale-Revised (FSDS-R):

The FSDS (original version) is a self-report questionnaire developed to measure sexually related personal distress in women. Response choices are “never,” “rarely,” “occasionally,” “frequently,” and “always.” The questionnaire is scored by summing the item responses (scaled such that “never” equals 0 and “always” equals 4). The FSDS-R differs from the FSDS in that it includes one additional question that asks women to rate distress related to low sexual desire. This modification is more consistent with diagnosis of HSDD. Significant improvement in score indicates therapeutic efficacy.

Sexual Quality of Life—Female (SQoL-F):

The SQoL-F is an 18-item questionnaire developed to assess the sexual quality of life women, specifically to assess sexual confidence, emotional well-being and relationship issues. The instrument has been validated for use in a broad range of women with Female Sexual Arousal Disorder and Hypoactive Sexual Desire Disorder. Significant improvement in score indicates therapeutic efficacy.

Example 6

A pilot study was conducted to assess the optimal pH of topical phenylephrine solution required to elicit smooth muscle contraction on the skin. A series of 10% phenylephrine solutions were prepared in phosphate buffer solutions of varied pH. pH 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, and 6.6 were used. Areas of skin on the subjects forearm were marked with a surgical pen. 50 microliter of each solution were applied to the marked area of skin and allowed to dry. After one hour the sites of application were visually inspected for the appearance of the pilomotor effect (i.e., “goose bumps”). The results are summarized in the table below:

TABLE 7 pH of 10% Phenylephrine Solution Results after 1 hour 4.6 None 4.8 Slight 5.0 Strong 5.2 Strong 5.4 Strong 5.6 Slight 5.8 Slight 6.0 None 6.2 None 6.4 None 6.6 None

Example 7

Oxymetazoline HCl 0.1%, 0.2%, 0.5%. A study was conducted to assess the dosage of topical oxymetazoline solution required to elicit nipple erection and sensitivity. Five premenopausal subjects participated in the study. Subjects were not hypertensive, pregnant or breastfeeding. Three formulations were used: Formula A: 0.1% topical oxymetazoline hydrochloride solution; Formula B: 0.2% topical oxymetazoline hydrochloride solution; Formula C: 0.5% topical oxymetazoline hydrochloride solution.

The study was conducted over 3 days. On day 1, subjects were instructed to apply Formula A to both areolas. On day 2, subjects were instructed to apply Formula B to both areolas. On day 3, subjects were instructed to apply Formula C to both areolas. 0.1 mL of each formula was applied using a metered dosage dispenser to each areola. Table 8 summarizes the finding from this study. The 0.5% topical oxymetazoline solution (Formula C) elicited a clinical response in 4 out of 5 subjects while the 0.1% and 0.2% formulations (Formula A and B) failed to elicit a response. With the 0.5% topical oxymetazoline solution, response in nipple erection and sensitivity was obtained approximately within 1 hour and lasted over 8 hours.

TABLE 8 Subject Nr. Formula A Formula B Formula C 1 NR NR R 2 NR NR NR 3 NR NR R 4 NR NR R 5 NR NR R R = response, i.e., nipple erection/increased sensitivity NR = no response

Due to the long acting effect of oxymetazoline it may be beneficial to apply once daily, every other day, or as needed prior to sexual activity or for restoration of sensation for patients that have lost or reduced sensitivity due to surgery or breast trauma.

Example 8

Phenylephrine HCl 15%. A study was conducted to evaluate the effect of Phenylephrine HCl 15% on the FSFI orgasm domain. Three premenopausal subjects participated in the study. Subjects were not hypertensive, pregnant or breastfeeding.

TABLE 9 Phenylephrine FSFI Orgasm Domain Study FSFI Scale How FSFI Scale How Often Orgasm Difficult to Reach was Reached Inter- Orgasm Inter- Subject Nr. Baseline vention Baseline vention 1 2 4 4 5 2 1 4 3 4 3 2 5 2 5

In addition, 3 of 5 subjects that have previously reported to experience no increased sensitivity or nipple erection following application of 10% Phenylephrine HCl, have reported increased sensitivity and nipple erection following application of 15% Phenylephrine HCl. No adverse events were reported.

Due to the shorter lasting acting effect of phenylephrine compared to oxymetazoline it may be beneficial to apply as needed prior to sexual activity. However, due to report of nipple sensitivity as long as 12 hours past application, it may be beneficial to apply phenylephrine daily.

Example 9 Synephrine HCl 50%.

A study was conducted to assess the dosage of topical synephrine solution required to elicit nipple erection and sensitivity. Five premenopausal subjects participated in the study. Subjects were not hypertensive, pregnant or breastfeeding. Two formulations were used: Formula A: 40% topical synephrine hydrochloride solution; Formula B: 50% topical synephrine hydrochloride solution.

The study was conducted over 2 days. On day 1, subjects were instructed to apply Formula A to both areolas. On day 2, subjects were instructed to apply Formula B to both areolas. 0.1 mL of each formula was applied using a metered dosage dispenser to each areola. Table 10 summarizes the finding from this study. The 50% topical synephrine hydrochloride solution (Formula B) elicited a clinical response in 4 out of 5 subjects while Formula A failed to elicit a response.

TABLE 10 Synephrine Study Subject Nr. Formula A Formula B 1 NR R 2 NR R 3 NR R 4 NR NR 5 NR R NR = No Response R = Response i.e., nipple erection/increased sensitivity

Example 10

Erection of the Nipple Areola Complex with 1% Phenylephrine Hydrochloride Solution

In the following experiment, a commercially available iontophoresis patch was used to erect the nipple of a female subject.

1. The nipple and areola of each breast were prepared by cleaning with a sterile alcohol pad.

2. Two Inotopatch 80 (Travanti Medical) patches were removed from packaging.

3. The positive electrode of the first patch was filled with 1.3 mL of a 1% phenylephrine hydrochloride.

4. The negative electrode of the first patch was filled with 1.3 mL of a saline solution.

5. The positive electrode (approximately 1.5 cm diameter) containing the drug was placed over the nipple areola complex of the right breast; the negative electrode was placed on the adjacent breast tissue outside the nipple areola complex of the right breast.

6. Steps 2-5 were repeated, however, both electrodes of the Inotopatch 80 were filled with 1.3 mL of saline. The patch was applied to left breast following the procedure of step 5.

7. The patches were left in place (adhesive) for 1 hour (dosage=4.8 A, 80 mA/min).

8. After 1 hour the patches were removed.

After the experiment above, the patient's right nipple was visibly erect; the left nipple was not. The patient described increased sensitivity in the right nipple compared to the left nipple.

Example 11 Restoration of Nipple Sensitivity Post Breast Surgery.

A case study was conducted to assess the efficacy of a topical phenylephrine solution in increasing nipple sensitivity in patients that reported a loss in nipple sensitivity post breast surgery. Five subjects ages 36-65 participated in the study. Subjects were asked to rate their nipple sensitivity on a Likert scale (1-10) before surgery and currently (i.e., after surgery). Next, patients were asked to apply a 10% phenylephrine solution to each nipple areola complex. 45 minutes after application of the drug, patients were asked again to rate their nipple sensitivity on a Likert scale (1-10). The results of the study are summarized in Table 11 below.

TABLE 11 Nipple Sensitivity Post- Breast Pre- Post- Surgery + Patient Age Size Surgery Type Surgery Surgery Drug 1 65 34 DD Lumpectomy 10 3 8 2 38 36 D Augmentation 9 5 8 3 42 36 C Augmentation, 8 5 6 Lift 4 36 30 C Augmentation 8 6 6 5 52 38 C Lumpectomy, 7 0 1 Reduction, Partial Masectomy, Trans Flap

Example 12

10%, 15% and 20% Phenylephrine Solutions Applied to Nipple-Areola Complex.

Method:

20 healthy, pre-menopausal females were recruited to the study. Subjects were instructed to apply either 4 or 6 drops of an investigational drug to each nipple areola complex. Baseline blood-pressure, heart rate, nipple erection, nipple sensitivity, genital lubrication and arousal were measured and recorded. 30 minutes later, blood pressure and heart rate were measured and recorded. 60 minutes later, blood-pressure, heart rate, nipple erection, nipple sensitivity, genital lubrication and arousal were measured and recorded.

During the study, four parameters of efficacy were measured: nipple erection, nipple sensitivity, genital lubrication, and arousal. Efficacy parameters were all patient reported outcomes measured at 0 and 60 minutes after the application of the investigational drug. Nipple erection was determined by asking the patient if they had experienced nipple erection during the 60 minutes after the application of the investigational drug. Nipple sensitivity was measured with a Likert scale of 1-10 (1 being “insensitive”, 10 being “extremely sensitive/bordering on pain”) at 0 and 60 minutes after the application of the investigational drug. Genital lubrication was measured with a Likert scale of 1-10 (1 being “none”, 10 being “excellent”) at 0 and 60 minutes after the application of the investigational drug. Arousal was measured with a Likert scale of 1-10 (1 being “none”, 10 being “extremely aroused”) at 0 and 60 minutes after the application of the investigational drug. A summary of the efficacy data is presented in the table below.

After a 48-hour washout period, subjects repeated the procedure using 4 or 6 drops of a new arm of the study. The subjects and the investigator were blinded to the drug assignment in each arm. In total 6 arms were tested:

Arm 1—Placebo, 4 drops

Arm 2—10% Phenylephrine HCl, 4 drops

Arm 3—15% Phenylephrine HCl, 4 drops

Arm 4—20% Phenylephrine HCl, 4 drops

Arm 5—Placebo, 6 drops

Arm 6—10% Phenylephrine HCl, 6 drops

Results:

The tables below shows the results of the study. There were no changes in blood pressure or heart rate of any of the subjects participating in the study. There was one adverse event (nipple pain) observed in the 20% Phenylephrine arm.

TABLE 12 Nipple Erection and Sensitivity, Four Drops of Investigational Drug (0.114 mL) per NAC Placebo 10% PE 15% PE 20% PE Patient # Erection Sensitivity Erection Sensitivity Erection Sensibility Erection Sensitivity 1 0 2 0 0 0 0 1 4 2 0 −1   0 0 0 2 3 0 1 1 1 0 2 1 2 4 0 0 0 0 1 3 0 0 5 0 0 0 1 0 0 1 0 6 0 1 0 1 1 2 1 1 7 0 0 1 0 0 0 0 0 9 0 1 1 5 1 5 1 1 10 0 0 0 0 0 2 1 2 11 0 0 0 1 0 0 0 0 12 0 0 0 0 0 0 13 0 0 1 2 0 2 1 2 14 0 0 0 0 0 0 0 0 15 0 0 0 0 0 1 1 1 16 0 0 1 1 1 3 1 4 17 0 0 1 2 1 9 1 9 19 0 0 1 0 0 0 1 2 20 0 0 0 1 1 1 1 1 21 1 2 0 0 22 1 0 1 1 1 3 1 0 # Patients 18  18  19  19  19  19  19  19  Responders 0 1 7 3 8 10  13  8 % Responders    0%    6%  37%  16%  42%  53%  68%  42%

TABLE 13 Nipple Erection and Sensitivity, Six Drops of Investigational Drug (0.170 mL) per NAC Placebo 10% PE Patient # Erection Sensitivity Erection Sensitivity 1 0 0 0 2 2 3 0 0 1 2 4 0 0 1 4 5 0 0 0 0 6 1 1 0 1 7 0 0 0 0 9 1 3 1 3 10 0 0 1 2 11 0 0 12 0 0 0 0 13 1 1 0 0 14 0 0 0 0 15 0 0 16 0 0 1 4 17 1 3 19 0 0 1 1 20 1 1 21 22 # Patients 14 14 16 16 Responders 3 1 8 7 % Responders 21% 7% 50% 44%

Tables 12 and 13 demonstrate the dose dependent increase in nipple sensitivity after application of the investigational drug. Nipple erection data was scored “1” for a positive response to the question “Did you experience nipple erection after applying the solution?” It was scored “0” otherwise. Sensitivity data was tabulated by subtracting the patient reported nipple sensitivity at 60 minutes from the reported value at baseline. Subjects were asked to rate their level of nipple sensitivity on a scale of 1-10 (1 being “non-sensitive” and 10 being “extremely sensitive, bordering on pain.”) Subjects reporting a sensitivity increase greater than 2 after the application of each investigational drug were considered sensitivity responders.

TABLE 14 Change in heart rate 15, 30, and 60 minutes after the application of four drops of investigational drug (0.114 mL) per NAC Placebo Arm A 10% Arm C HR Delta HR HR Delta HR Patient # (t = 0) t = 15 t = 30 t = 60 (t = 0) t = 15 t = 30 t = 60 1 57 −5 2 −1 65 −2 0 −10 2 73 −9 −5 −1 63 −3 −2 −2 3 93 −1 −9 −1 90 −10 −12 −7 4 78 −6 0 −7 82 3 13 −1 5 70 7 −2 −2 85 −7 −7 −6 6 68 1 −4 1 72 0 −3 −4 7 68 4 −7 −3 68 3 −7 −4 8 80 10 7 8 74 0 −1 −1 9 63 −4 −9 0 60 3 5 5 10 80 −7 1 −3 68 −1 7 5 11 73 −5 −6 −8 71 −2 −3 −8 12 96 2 −4 −7 74 3 3 7 13 85 −2 −5 2 85 4 3 2 14 102 −3 −9 −13 96 −9 −4 2 15 65 −6 −4 −6 66 −3 −4 −1 16 80 −10 −10 −12 77 −2 −4 −9 17 61 −6 −5 −5 61 −1 −1 −4 18 88 0 −1 0 83 6 −7 −2 19 68 −1 −3 6 74 −5 0 −4 20 87 −3 −8 −2 85 0 7 −6 15% (Arm D) 20% (Arm B) HR Delta HR HR Delta HR Patient # (t = 0) t = 15 t = 30 t = 60 (t = 0) t = 15 t = 30 t = 60 1 77 −9 −14 −16 84 −15 −20 −21 2 63 1 4 4 64 3 4 3 3 96 0 0 −6 84 −2 −6 1 4 77 −4 −1 −2 79 −1 −14 −13 5 82 −6 −2 −4 71 −2 −3 −21 6 71 4 6 −2 82 −6 7 6 7 80 −15 −10 −7 70 2 1 −1 8 89 −9 −10 −9 81 −4 7 0 9 80 −4 −4 1 80 −10 −1 −8 10 82 −8 −5 −3 82 6 −7 −6 11 82 −5 −2 −2 66 1 10 4 12 79 −3 2 0 80 −7 −9 0 13 92 −9 −12 −10 82 −5 1 −3 14 87 6 8 −6 102 −6 −1 −4 15 71 −1 5 −3 61 −1 3 4 16 72 −2 −2 −2 60 10 10 11 17 55 1 1 2 61 −4 −3 −3 18 76 −3 4 0 99 −3 −9 −6 19 76 −3 3 −6 67 7 6 9 20 80 −9 −8 −11 71 0 1 −2

TABLE 15 Genital lubrication and arousal, 60 minutes after the application of different phenylephrine solutions. Placebo (Arm A) 10% (Arm C) 15% (Arm D) 20% (Arm B) Patient # Lubrication Arousal Lubrication Arousal Lubrication Arousal Lubrication Arousal 1 0 0 0 0 0 0 1 1 2 −1   −1   0 0 1 0 0 0 3 1 0 1 0 3 0 3 0 4 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 0 0 7 −2   0 0 0 0 0 2 0 8 1 0 1 0 2 0 0 0 9 0 0 0 0 0 0 0 0 10 0 0 0 0 0 0 0 0 11 0 0 0 0 0 0 0 0 12 0 0 0 0 0 0 0 0 13 0 0 0 0 0 0 0 0 14 1 0 0 0 1 0 2 0 15 0 0 0 0 0 0 0 0 16 0 0 0 0 0 0 2 0 17 0 0 0 0 0 −1   0 0 18 0 0 0 0 0 0 0 0 19 0 0 2 0 0 0 0 0 20 0 0 0 0 1 0 0 0 # Patients 20  20  20  20  20  20  20  20  Responders 0 0 1 0 2 0 4 0 Percent    0%    0%    5%    0%  10%    0%  20%    0%

Genital lubrication was measured with a Likert scale of 1-10 (1 being “none” and 10 being “excellent”) at 0 and 60 minutes after the application of the investigational drug. Arousal was measured with a Likert scale of 1-10 (1 being “none” and 10 being “extremely aroused”) at 0 and 60 minutes after the application of the investigational drug. Data are displayed as change from baseline of the reported values. A subject was considered a responder for genital lubrication if she reported a change in genital lubrication of 2 or more.

A subject was considered a responder for arousal if she reported a change in arousal of 2 or more.

Example 13

A study was conducted to assess the effectiveness of different acetylcholine receptor agonists on eliciting nipple erection and increasing nipple sensitivity in normal women aged 18-65. Ten subjects were recruited. Each subject was randomly assigned a single agonist. Each subject self-administered a single dose of the agonist to one NAC that was self-reported as the least sensitive (or if no differential sensitivity, then the left NAC). The agonists were applied in topical solutions to the NAC. The subject was supervised by a medical professional. Blood pressure and heart rate were monitored at baseline, 5 minutes, 10 minutes, and 30 minutes. No changes in blood pressure or heart rate were detected. Subjects were asked to report if they experienced nipple erection and sensitivity in less than 10 minutes and if the effect lasted more or less than 10 minutes. The results are reported in Table 16. The subjects all responded to the agonists. The effect was short-lived; however, sensitivity is some of the subjects was reported up 60 minutes later.

TABLE 16 Response to acetylcholine receptor agonists. Nipple Sensitivity Nipple Onset Effect Nipple Sensi- Time Duration Erection tivity Dosage Agent (min) (min) (Yes/No) (Yes/No) (mg/cm²) Acetylcholine <10 <5 Yes Yes 1.3 Nicotine <10 <10 Yes Yes 5.0 Alpha-Lobeline <10 <10 Yes Yes 1.9 Mecholyl <10 <10 Yes Yes 2.0 Pilocarpine <10 <5 Yes Yes 6.3 Carbachol <10 <10 Yes Yes 0.6 Cevimeline <10 <10 Yes Yes 5.6 Bethanechol <10 <10 Yes Yes 12.5 Methacholine <10 <10 Yes Yes 0.4 Metaclopramide <10 <10 Yes Yes 3.8

Example 14 A. Measurement of Nipple Sensitivity: Patient Reported Outcomes (PRO)

-   Nipple sensitivity will be measured using the following PRO efficacy     parameters:

Nipple Erection:

-   Each subject will complete a self-report assessment as to whether or     not her nipple is erect.

Nipple Sensitivity:

-   Each subject will self-report her nipple sensitivity on a Likert     scale of 1 to 10: 1 being insensitive, 10 being extremely sensitive     bordering on uncomfortable/pain.

Nipple Pain:

-   Each subject will self-report if she is experiencing nipple pain.

B. Measurement of Nipple Sensitivity: Quantitative Measurements

-   Nipple sensitivity will also be measured using quantitative     sensitivity measurements such as the following. Skin sensitivity     tests will be performed by the primary investigator in a quiet     environment. During the test, subjects will lay on a comfortable bed     with their eyes closed. The areola will be divided into four     quadrants, with the nipple considered an additional point, for a     total of five regions (FIG. 1). In each region, four sensory     modalities will be tested: light touch, temperature (hot and cold),     vibration, and pressure. The quantitative measurements will occur at     baseline, 30, and 60 minutes following application of the     interventional drug.

Light Touch Modality:

Sensitivity to light touch will be tested using a wad of cotton wool passed smoothly over the skin. The subject will be asked to report feeling the application of the cotton wad.

Temperature Modality:

Temperature sensitivity will be tested with tubes containing water heated at 60° C. and crushed ice, respectively, placed on the skin for two seconds. Subjects will be asked to report if they can feel each applied tube.

Vibration Modality:

A tuning fork vibrating at 128 vibrations per second placed in contact with the skin for two seconds. Subjects will be asked to report if they can feel vibrations.

Pressure Modality:

Pressure sensitivity will be measured using Semmes-Weinstein monofilaments (Fabrication Enterprises, Inc.), corresponding to threshold/potential skin pressure values of 0.05, 0.2, 2, 4, 10, and 300 grams. The monofilament is used to exert pressure until it is bent, and the pressure is maintained for 5 seconds. Starting with the lightest filament, subjects will be asked to report if they can feel each of the monofilaments in a stepwise fashion. The lowest value will be recorded as the pressure threshold for the region. 

1. A method of increasing sexual satisfaction in a female subject comprising applying a therapeutically effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of the female subject.
 2. The method of claim 1, wherein the method results in the female subject having increased sexual self-esteem, increased self-perception of femininity, and/or increased self-esteem.
 3. The method of claim 1, wherein the female subject has undergone breast surgery prior to application of the active agent and the surgery resulted in a reduction of nipple sensitivity.
 4. The method of claim 1, wherein the active agent is applied in a sufficient amount to cause erection of the nipple or increased nipple sensitivity.
 5. The method of claim 1, or wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of muscarinic acetylcholine receptor M₂ agonists and muscarinic acetylcholine receptor M₃ agonists.
 6. The method of claim 1, or wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium, methacholine, aceclidine, pilocarpine, and muscarine.
 7. The method of claim 1, or wherein the active agent is a nicotinic acetylcholine receptor agonist selected from the group consisting of varenicline tartrate, galantamine hydrobromide, nicotine, carbachol, suxamethonium chloride (succinylcholine chloride), and epibatidine.
 8. The method of claim 1, or wherein the active agent is a cholinesterase inhibitor selected from the group consisting of physostigmine, neostigmine, edrophonium, pyridostigmine, echotihiophate, ambenonium, demecarium, tacrine, donepezil, rivastigmine, galantamine, and pralidoxime.
 9. The method of claim 1, wherein the female subject has reduced sensitivity at the nipple-areola complex before applying the active agent.
 10. A method of treating female sexual dysfunction, the method comprising applying a therapeutically effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of a female subject in need of such treatment.
 11. The method of claim 10, wherein the composition is applied in a sufficient amount to cause erection of the nipple or increased nipple sensitivity.
 12. The method of claim 10, wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of muscarinic acetylcholine receptor M₂ agonists and muscarinic acetylcholine receptor M₃ agonists.
 13. The method of claim 10, wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium, methacholine, aceclidine, pilocarpine, and muscarine.
 14. The method of claim 10, wherein the active agent is a nicotinic acetylcholine receptor agonist selected from the group consisting of varenicline tartrate, galantamine hydrobromide, nicotine, carbachol, suxamethonium chloride (succinylcholine chloride), and epibatidine.
 15. The method of claim 10, wherein the active agent is a cholinesterase inhibitor selected from the group consisting of physostigmine, neostigmine, edrophonium, pyridostigmine, echotihiophate, ambenonium, demecarium, tacrine, donepezil, rivastigmine, galantamine, and pralidoxime.
 16. The method of claim 10, wherein the female sexual dysfunction is selected from the group consisting of female sexual arousal disorder (FSAD), female sexual interest/arousal disorder (FSIAD), female orgasmic disorder (FOD) and female hypoactive sexual desire disorder (FHSDD).
 17. A method of reducing or alleviating a symptom of female sexual dysfunction, the method comprising applying a therapeutically effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of a female subject in need of such treatment.
 18. The method of claim 17, wherein the symptom of female sexual dysfunction is a symptom of female hypoactive sexual desire disorder (FHSDD), female sexual interest/arousal disorder (FSIAD), female orgasmic disorder (FOD) or female sexual arousal disorder (FSAD).
 19. The method of claim 17, wherein the symptom of female sexual dysfunction is a symptom of female sexual interest/arousal disorder selected from the group consisting of (1) absent/reduced interest in sexual activity; (2) absent/reduced sexual/erotic thoughts or fantasies; (3) no/reduced initiation of sexual activity, and typically unreceptive to a partner's attempts to initiate; (4) absent/reduced sexual excitement/pleasure during sexual activity in almost all or all sexual encounters; (5) absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues; and (6) absent/reduced genital or nongenital sensations during sexual activity in almost all or all sexual encounters.
 20. The method of claim 17, wherein the active agent is applied in a sufficient amount to cause erection of the nipple or increased nipple sensitivity.
 21. The method of claim 17, wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of muscarinic acetylcholine receptor M₂ agonists and muscarinic acetylcholine receptor M₃ agonists.
 22. The method of claim 17, wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium, methacholine, aceclidine, pilocarpine, and muscarine.
 23. The method of claim 17, wherein the active agent is a nicotinic acetylcholine receptor agonist selected from the group consisting of varenicline tartrate, galantamine hydrobromide, nicotine, carbachol, suxamethonium chloride (succinylcholine chloride), and epibatidine.
 24. The method of claim 17, wherein the active agent is a cholinesterase inhibitor selected from the group consisting of physostigmine, neostigmine, edrophonium, pyridostigmine, echotihiophate, ambenonium, demecarium, tacrine, donepezil, rivastigmine, galantamine, and pralidoxime.
 25. A method of causing erection of nipples, increasing nipple sensitivity, increasing duration of orgasm, reducing time to orgasm, and/or increasing oxytocin release related to sexual activity in a female subject comprising applying an effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of the female subject.
 26. The method of claim 25, wherein the method is to increase nipple sensitivity in a female subject that had breast surgery.
 27. The method of claim 25, wherein the method is to increase nipple sensitivity in a female subject who has not undergone breast surgery.
 28. A method for treating neuropathy in the nipple areola complex in a female subject comprising applying an effective amount of an active agent selected from the group consisting of muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors topically to a nipple-areola complex of the female subject.
 29. The method of claim 25, wherein the active agent is applied in a sufficient amount to cause erection of the nipple.
 30. The method of claim 25, wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of muscarinic acetylcholine receptor M₂ agonists and muscarinic acetylcholine receptor M₃ agonists.
 31. The method of claim 25, wherein the active agent is a muscarinic acetylcholine receptor agonist selected from the group consisting of NNC 11-1585, NNC 11-1607, pentylthio-TZTP, NNC 11-1314, xanomeline, sabcomeline, arecaidine propargyl ester, acetylcholine, arecoline, oxotremorine, McN-A-343, milameline, oxotremorine-M, methylfurmethide, bethanechol, carbachol, furtrethonium, methacholine, aceclidine, pilocarpine, and muscarine.
 32. The method of claim 25, wherein the active agent is a nicotinic acetylcholine receptor agonist selected from the group consisting of varenicline tartrate, galantamine hydrobromide, nicotine, carbachol, suxamethonium chloride (succinylcholine chloride), and epibatidine.
 33. The method of claim 25, wherein the active agent is a cholinesterase inhibitor selected from the group consisting of physostigmine, neostigmine, edrophonium, pyridostigmine, echotihiophate, ambenonium, demecarium, tacrine, donepezil, rivastigmine, galantamine, and pralidoxime.
 34. The method of one of claim 1, wherein the composition is applied within one hour prior to a sexual activity.
 35. The method of one of claim 1, wherein the subject is a premenopausal female. 